Cycloalkyl-substituted aminomethylpyrrolidine derivatives

ABSTRACT

This invention provides a quinolone derivative which exerts strong antibacterial action upon various bacteria and has high safety, and it relates to a compound having a structure of formula (I), its salts and hydrates thereof:                    
     {R 1  and R 2 : hydrogen, alkyl; n: 1 to 4; Q: following structure (Ia):                    
     [R 3 : alkyl, alkenyl, halogenoalkyl, cyclic alkyl, aryl, heteroaryl, alkoxyl, alkylamino; R 4 : hydrogen, alkylthio; R 5 : hydrogen, amino, hydroxyl, thiol, halogenomethyl, alkyl, alkenyl, alkynyl, alkoxyl; X 1 : halogen, hydrogen, A 1 : nitrogen, structure of formula (II):                    
     (X 2 : hydrogen, amino, halogen, cyano, halogenomethyl, halogenomethyl, alkyl, alkenyl, alkynyl, alkoxyl; R 4  and R 3  or X 2  and R 3  may together form a cyclic structure; Y: hydrogen, various ester forming groups]}.

TECHNICAL FIELD

This invention relates to a synthetic quinolone antibacterial agentuseful as a drug for humans, animals or fishes or an antibacterialpreservative.

This invention also relates to a synthetic quinolone antibacterial agentin which the structure of substituent at the 7 position of1,4-dihydro-4-oxoquinoline skeleton or at the 10-position of2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton exertsimportant influence upon the expression of pharmacological effects suchas antibacterial activity, pharmacokinetics and safety, having a3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group which can provideexcellent antibacterial activity, pharmacokinetics and safety, as asubstituent at the 7- or 10-position, and also having excellentantibacterial activity, proper pharmacokinetics and high safety, namelyto a6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid derivative or a2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylicacid derivative, and to an antibacterial agent and an antibacterialpreparation, which contain the compound.

BACKGROUND ART

Since the discovery of Norfloxacin, antibacterial activity andpharmacokinetics of synthetic quinolone antibacterial agents have beenimproved, and many compounds are now used in the clinical field aschemotherapeutic agents which are effective in almost systemicinfectious diseases.

In recent years, generation of bacteria having low sensitivity tosynthetic quinolone antibacterial agents has been increasing in thefield of clinics. For example, like the case of Staphylococcus aureus(MRSA) and pneumococcus (PRSP) which are non-sensitive to β-lactamantibiotics and enterococcus (VRE) which is non-sensitive toaminoglycoside antibacterial agents, a case has been increasing in whicha Gram-positive bacterium originally resistant to drugs other thansynthetic quinolone antibacterial agents becomes low-sensitive tosynthetic quinolone antibacterial agents too. In consequence,development of a drug having further high efficacy has been called forin the field of clinics. On the other hand, it has been revealed thatsynthetic quinolone antibacterial agents cause a side effect in whichconvulsion is induced when a non-steroidal anti-inflammatory drug issimultaneously used, as well as other side effects such asphototoxicity, so that development of a synthetic quinoloneantibacterial agent having further high safety has also been called forin the field.

It is known that structures of substituents at the 7-position and1-position have a great influence to the antibacterial activity,pharmcokinetics and safety of synthetic quinolone antibacterial agents.It is already known that quinolone derivatives having3-aminamethylpyrrolidine as a substituent show strong antibacterialactivity for Gram-negative and Gram-positive bacteria. For example, a7-(3-ainomethylpyrrolidin-1-yl)quinolonecarboxylic acid derivative isdescribed in Journal of Medicinal Chemistry, vol. 29, p. 445 (1986), a7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl)quinolonecarboxylic acidderivative is described in Journal of Medicinal Chemistry, vol. 37, p.733 (1994), and a 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolonecarboxylicacid derivative is described in Chemical& Pharmaceutical Bulletin, vol.42, p. 1442 (1994). However, no compounds are known which have a3-(1-amino-1-cycloalkyl)methylpyridin-1-yl group at the 7-position andare also related to the present invention.

On the other hand, quinolone derivatives having 3-aminomethylpyrrolidineas a substituent are compounds which show strong antibacterial activity,but, since most of these compounds have low selective toxicity, they actupon not only bacteria but also eucaryotic cells so that it is difficultto use them as medical drugs or animal drugs.

Also, it is known that quinolone derivatives having a 3-aminopyrrolidinederivative at the 7-position and 2-(S)-fluoro-1-(R)-cyclopropyl group atthe 1-position of the quinoline skeleton have weaker micronucleusinducing toxicity than those corresponding 1-cyclopropylquinolonederivatives. Their examples are described in Journal of MedicinalChemistry, vol. 37. P. 3344 (1994).

On the other hand, quinolonecarboxylic acid derivatives having a3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group as a substituent,which are related to the present invention, are exemplified for examplein JP-W-3-502452 (the term “JP-W” as used herein means an “unexaminedpublished Japanese international patent application”), and it describescompounds represented by a formula (a) or (b) shown below. However,substituent at the 5-position of these exemplified quinolones is limitedto a straight, branched or cyclic lower alkyl having 1 to 3 carbonatoms, and JP-W-3-502452 does not describe compounds having the1-[2-(S)-fluoro-1-(R)-cyclopropyl]quinoline skeleton or3-(S)-methyl-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton related to thepresent invention. In addition, JP-W-3-502452 does not discloseillustrative examples of the3-[1-amino-1-cycloalkyl]methylpyrrolidin-1-yl group.

[In the above formula, R₇ is an alkyl having 1 to 4 carbon atoms, avinyl, a haloalkyl, a hydroxyalkyl having 2 to 4 carbon atoms, acycloalkyl having 3 to 6 carbon atoms, a phenyl or a phenyl substitutedwith a halogen, an alkyl, NH₂ or OH, R₆ is a straight, branched orcyclic lower alkyl having 1 to 3 carbon atoms, and X₃ is CH, CF, CCl,CBr, N, CCF₃, CNH₂, CNO₂, CR or COR′ (in these formulae, R is a loweralkyl and R′ is hydrogen or a lower alkyl). Definitions of substituentsof the compound of formula (a) are independent to those the compound ofthe present invention.]

In the above formula, Z is a group represented by the following formula(b).

(In this formula, m is an integer of from 0 to 4, and the substituentsR₉ and R₁₀ are each independently a hydrogen atom, a lower alkyl or acycloalkyl. Definitions of substituents of the compound of formula (b)are independent to those the compound of the present invention.)

In addition, PCT WO 96/39407 discloses compounds represented by thefollowing formula (c), but they are limited to 2-pyridone derivativessuch as 4H-4-oxoquinotozone skeleton, and PCT WO 96/39407 does notdescribe compounds having the 1,4-dihydro-4-oxoquinoline skeleton or2,3-dihydro-3-(S)-ethyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazineskeleton related to the present invention. Also, PCT WO 96/39407 doesnot disclose illustrative examples of optically active3-[1-amino-1-cyclopropyl]methylpyrrolidin-1-yl group.

In addition, PCT WO 96/39407 does not describe about safety of thecompounds of formula (c).

DISCLOSURE OF INVENTION

In view of the above, the inventors of the present invention haveconducted intensive studies with the aim of providing the field ofclinics with a compound which has excellent antibacterial activity, highefficacy and excellent safety. As a result of the extensiveinvestigation, it has been found absolutely unexpectedly that acycloalkyl-substituted aminomethylpyrrolidine derivative represented bythe formula (I) described below, its salts and hydrates thereof can showstrong antibacterial activity upon broad range of Gram-negative andGram-positive bacteria, can show particularly strong antibacterialactivity upon resistant strains of Gram-positive bacteria includingMRSA, PRSP and VRE, and also have excellent safety and goodpharmacokinetics, thereby resulting in the accomplishment of the presentinvention.

Particularly, it has been found that a compound represented by thefollowing formula (I) in which a cycloalkyl-substitutedaminomethylpyrrolidine derivative is introduced at the 7position of the1[2-(S)-fluoro-1-(R)-cyclopropyl]quinoline skeleton, its salts andhydrates thereof show broad and excellent antibacterial activity uponany one of Gram-negative and Gram-positive bacteria includingdrug-resistant strains, have excellent safety with sharply attenuatedmicronucleus induction action, and also have excellent pharmacokinetics.

Accordingly, the present invention relates to a compound represented bythe following formula (I), its salts and hydrates thereof:

{wherein R¹ and R² each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms, in which the alkyl group mayhave one or more substituents selected from the group consisting of ahydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbonatoms and an alkyloxy group; n is an integer of 1 to 4; and Q is apartial structure represented by the following formula (Ia):

[wherein R³ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms whichmay have a substituent, an aryl group which may have a substituent, aheteroaryl group which may have a substituent, an alkoxyl group having 1to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms;

R⁴ represents a hydrogen atom or an alkylthio group having 1 to 6 carbonatoms;

R⁴ and the aforementioned R³ may form together with a part of the motherskeleton a ring structure optionally containing a sulfur atom as a ringconstituting atom thereof and optionally having an alkyl group having 1to 6 carbon atoms as a substituent;

R⁵ represents a hydrogen atom, an amino group, a hydroxyl group, a thiolgroup, a halogenomethyl group, an alkyl group having 1 to 6 carbonatoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl grouphaving 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbonatoms, in which the amino group may have one or more substituentsselected from the group consisting of formyl group, an alkyl grouphaving 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms;

X¹ represents a halogen atom or a hydrogen atom,

A¹ represents a nitrogen atom or a partial structure represented byformula (II):

(wherein x² represents a hydrogen atom, an amino group, a halogen atom,a cyano group, a halogenomethyl group, a halogenamethoxyl group, analkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxylgroup having 1 to 6 carbon atoms, in which the amino group may have oneor more substituents selected from the group consisting of a formylgroup, an alkyl group having 1 to 6 carbon atoms and an acyl grouphaving 2 to 5 carbon atoms; and

X² and the aforementioned R³ may form together with a part of the motherskeleton a ring structure optionally containing an oxygen atom, anitrogen atom or a sulfur atom as a ring constituting atom thereof andoptionally having an alkyl group having 1 to 6 carbon atoms as asubstituent); and

Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, apivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, adimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene grouphaving 1 to 6 carbon atoms and a phenyl group]}.

The present invention also relates to each of the following items.

A compound, its salts and hydrates thereof, wherein Q in the formula (I)is a6-caxboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazin-10-ylgroup;

the aforementioned compound, its salts and hydrates thereof, wherein thecompound of formula (I) is a stereochemically pure compound;

the aforementioned compound, its salts and hydrates thereof, wherein R³in the formula (I) is a halogenocyclopropyl group;

the aforementioned compound, its salts and hydrates thereof, wherein thehalogenocyclopropyl group in the formula (I) is a1,2-cis-halogenocyclopropyl group;

the aforementioned compound, its salts and hydrates thereof, wherein thehalogenocyclopropyl group in the formula (I) is a stereochemically puresubstituent;

the aforementioned compound, its salts and hydrates thereof, wherein thehalogenocyclopropyl group in the formula (I) is a(1R,2S)-2-halogenocyclopropyl group;

the aforementioned compound, its salts and hydrates thereof, wherein thehalogen atom of the halogenocyclopropyl group in the formula (I) is afluorine atom;

the aforementioned compound, its salts and hydrates thereof, wherein thecompound of formula (I) is a stereochemically pure compound;

the aforementioned compound, its salts and hydrates thereof, wherein nin the formula (I) is 1;

the aforementioned compound, its salts and hydrates thereof, wherein thecompound of formula (I) is a stereochemically pure compound;

7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts and hydrates thereof;5-amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts and hydrates thereof;

5-amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts and hydrates thereof; the aforementioned compound, itssalts and hydrates thereof, wherein Y is a hydrogen atom;

a drug containing the aforementioned compound, its salts and hydratesthereof as an active ingredient; and

an antibacterial agent containing the aforementioned compound, its saltsand hydrates thereof as an active ingredient.

EMBODIMENT FOR CARRYING OUT INVENTION

Each of the substituents of the compound of the present inventionrepresented by formula (I):

(wherein R¹, R², n and Q are as defined in the foregoing) will beexplained in the following.

The substituents R¹ and R² is each independently a hydrogen atom or analkyl group having 1 to 6 carbon atoms, wherein the alkyl group may haveone or more substituents selected from the group consisting of ahydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbonatoms and an alkyloxy group.

The alkyl group may be either straight or branched group having 1 to 6carbon atoms, and the preferred examples thereof are methyl, ethyl,normal propyl and isopropyl groups.

When the alkyl group has a hydroxyl group as a substituent, the alkylgroup may be either straight or branched form having 1 to 6 carbonatoms, and the hydroxyl group may preferably be substituted on theterminal carbon atom of the alkyl group. Preferred examples of the allylgroup having a hydroxyl group include those which have 1 to 3 carbonatoms, such as a hydroxymethyl group, a 2-hydroxyethyl group, a2-hydroxypropyl group and a 3-hydroxypropyl group.

When the alkyl group has a halogen atom as a substituent, the alkylgroup may be either straight or branched form having 1 to 6 carbonatoms, and a fluorine atom is desirable as the halogen atom. With regardto the number of fluorine atoms, it may be any one of frommono-substitution to perfluoro substitution. The examples thereof aremonofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2-difluoroethyl and 2,2,2-trifluoroethyl groups. Among these groups, amonofluoromethyl group and a 2-fluoroethyl group are more preferred.

When the alkyl group has an alkylthio group as a substituent, the alkylgroup may be either straight or branched form having 1 to 6 carbonatoms, and the alkylthio group may also be either straight or branchedform having 1 to 6 carbon atoms. An alkylthiomethyl group, analkylthioethyl group and an alkylthiopropyl group are desirable as thealkyl group having an alkylthio group, and the alkylthio group maypreferably have 1 to 3 carbon atoms. More preferred examples are amethylthiomethyl group, an ethylthiomethyl group and a methylthioethylgroup.

When the alkyl group has an alkoxyl group as a substituent, the alkylgroup may be either straight or branched form having 1 to 6 carbonatoms, and the alkoxyl group may also be either straight or branchedform having 1 to 6 carbon atoms. An alkoxymethyl group, an alkoxyethylgroup and an alkoxypropyl group are desirable as the alkyl group havingan alkoxyl group, and the alkoxyl group may preferably have up to 3carbon atoms. More preferred examples thereof are a methoxymethyl group,an ethoxymethyl group and a methoxyethyl group.

The symbol n is an integer of from 1 to 4, preferably 1 or 2, and morepreferably 1.

Q is a partial structure represented by the following formula (Ia).

In the above formula (Ia), R³ is an alkyl group having 1 to 6 carbonatoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkylgroup having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6carbon atoms which may have a substituent, an aryl group which may havea substituent, a heteroaryl group which may have a substituent, analkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1to 6 carbon atoms.

In this case, an ethyl group is particularly desirable as the alkylgroup having 1 to 6 carbon atoms. As the alkenyl group having 2 to 6carbon atoms, a vinyl group or a 1-isopropenyl group is desirable. A2-fluoroethyl group is desirable as the halogenoalkyl group having 1 to6 carbon atoms. A cyclopropyl group is particularly desirable as thecyclic alkyl group, and a halogen atom, particularly a fluorine atom, isdesirable as the substituent of the cyclic alkyl group.

Examples of the aryl group which may have a substituent are a phenylgroup which may have 1 to 3 substituents selected from the groupconsisting for example of fluorine, chlorine, bromine or the likehalogen atom, a hydroxyl group, an amino group, a nitro group, an alkylgroup having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6carbon atoms, and its preferred illustrative examples are a phenylgroup, a 2-fluorophenyl group, a 4-fluorophenyl group, a2,4-difluorophenyl group, a 2-fluoro-4-hydroxyphenyl group, a3-amino-4,6-difluorophenyl group and a 4,6-difluoro-3 methylaminophenylgroup.

The heteroaryl group is a compound derived from a five or six-memberedaromatic heterocyclic compound which contains one or more hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom.Examples thereof are a pyridyl group and a pyrimidyl group. As thesubstituent on these rings, an alkyl group, a halogen atom or the likeis desirable. Particularly preferred is a 5-amino-2,4-difluoropyridylgroup.

A methoxyl group is desirable as the alkoxyl group having 1 to 6 carbonatoms. A methylamino group is desirable as the alkylamino group having 1to 6 carbon atoms.

As the substituent R³, a cyclic alkyl group or a halogenocycloalkylgroup is desirable. Among these groups, a cyclopropyl group or a2-halogenocyclopropyl group is particularly desirable. As the halogenatom, a fluorine atom is desirable.

The substituent R⁴ is a hydrogen atom or an alkylthio group having 1 to6 carbon atoms, or R³ and R⁴ may together form a ring structure byincorporating a part of the mother skeleton (namely by including thenitrogen atom to which R³ is bonded and the carbon atom to which R⁴ isbonded). The thus formed ring may contain a sulfur atom as itsconstituting atom, and the ring may further have an alkyl group having 1to 6 carbon atoms as a substituent. The ring to be formed herein mayhave a size of from four-membered ring to six-membered ring, and thering may be saturated or unsaturated.

The substituent X¹ is a halogen atom or a hydrogen atom, and a fluorineatom is desirable in the case of the halogen atom. Among these atoms, afluorine atom or a hydrogen atom is desirable as the substituent.

The substituent R⁵ is a hydrogen atom, an amino group, a hydroxyl group,a thiol group, a halogenomethyl group, an alkyl group having 1 to 6carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynylgroup having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6carbon atoms, wherein the amino group may have one or two substituentsselected from the group consisting of a formyl group, an alkyl grouphaving 1 to 6 carbon atoms and an acyl group having 2 to 6 carbon atoms.

The alkyl group may be either straight or branched group having 1 to 6carbon atoms, and its preferred examples are a methyl group, an ethylgroup, a normal propyl group and an isopropyl group. The alkenyl groupmay be either straight or branched group having 2 to 6 carbon atoms andis preferably a vinyl group. The alkynyl group may be either straight orbranched group having 2 to 6 carbon atoms and is preferably an ethynylgroup. A fluorine atom is particularly desirable as the halogen of thehalogenomethyl group, and its number may be from 1 to 3. The alkoxylgroup may have 1 to 6 carbon atoms and is preferably a methoxyl group.

The substituent ⁵ is preferably a hydrogen atom, an alkyl group or anamino group, of which a methyl group or an unsubstituted amino group ismore preferred.

When the substituent R⁵ is an amino group, a hydroxyl group or a thiolgroup, these groups may be protected with ordinally used protectivegroups.

Examples of such protective groups include tert-butoxycarbonyl,2,2,2-trichloroethoxycarbonyl and the like alkoxycarbonyl groups,benzyloxycarbonyl, para-methoxybenzyloxycarbonyl,para-nitrobenzyloxycarbonyl and the like aralkyloxycarbonyl groups,acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl,benzoyl and the like acyl groups, tert-butyl, benzyl, para-nitrobenzyl,para-methoxybenzyl, triphenylmethyl and the like alkyl or aralkylgroups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl,2,2,2-trichloroethoxymethyl and the like ethers and trimethylsilyl,isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl,tert-butyldiphenylsilyl and the like substituted silyl groups. Compoundswhose substituents are protected with these protective groups areparticularly useful as production intermediates.

When A¹ is a partial structure represented by formula (II):

X² is a hydrogen atom, an amino group, a halogen atom, a cyano group, ahalogenomethyl group, a halogenomethoxyl group, an alkyl group having 1to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, analkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to6 carbon atoms, wherein the amino group may have one or two substituentsselected from the group consisting of a formyl group, an alkyl grouphaving 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.

The alkyl group may be either straight or branched group having 1 to 6carbon atoms and the preferred examples thereof are a methyl group, anethyl group, a normal propyl group and an isopropyl group. The alkenylgroup may be either straight or branched group having 2 to 6 carbonatoms and is preferably a vinyl group. The alkynyl group may be eitherstraight or branched group having 2 to 6 carbon atoms and is preferablyan ethynyl group. A fluorine atom is particularly desirable as thehalogen of the halogenomethyl group, and its number may be from 1 to 3.The alkoxyl group may have 1 to 6 carbon atoms and is preferablymethoxyl group. A fluorine atom is particularly desirable as the halogenof the halogenamethoxyl group, and its number may be from 1 to 3.

Among these substituents, a halogen atom, an alkyl group or an alkoxylgroup is desirable, and a fluorine atom, a methyl group or a methoxylgroup is more desirable. These substituents are particularly desirablein the case where Q is the partial structure represented by the formula(Ia).

In addition, X² and the aforementioned R³ may together form ahydrocarbon ring structure (size of the ring may be from four-memberedring to seven-membered ring, and the ring may be saturated orunsaturated) by incorporating a part of the mother skeleton (namely byincluding the carbon atom to which X² is bonded and the nitrogen atom towhich R³ is bonded), and the thus formed ring may contain an oxygenatom, a nitrogen atom or a sulfur atom as its constituting atom, and thering may also have an alkyl group having 1 to 6 carbon atoms as asubstituent.

The partial structure represented by the aforementioned formula (Ia) isdesirable as Q. In this case, it is desirable that A¹ is the partialstructure of formula (II).

When Q is the partial structure of formula (Ia) and A¹ is the partialstructure of the formula (II), a preferred combination of R⁵ and X² is acase in which R⁵ is an amino group, a hydrogen atom, a hydroxyl group oran alkyl group having 1 to 6 carbon atoms and X² is a halogen atom, analkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6carbon atoms, a halogenomethoxyl group or a hydrogen atom.

A more preferred combination is a case in which R⁵ is an amino group, ahydrogen atom, a hydroxyl group or a methyl group and X² is a fluorineatom, a methyl group, a methoxyl group, a difluoramethoxyl group or ahydrogen atom.

A most preferred combination is a case in which R⁵ is an amino group, ahydrogen atom, a hydroxyl group or a methyl group and X² is a fluorineatom, a methyl group or a methoxyl group. For these R⁵ and X² groups, afluorine atom is desirable as X¹.

When the substituents X¹ and X² are halogen atoms, X¹ is particularlypreferably a fluorine atom and X² is preferably a fluorine atom or achlorine atom.

Next, the halogenocyclopropyl group of R³ will be explained.

As the substitutable halogen atom, a fluorine atom and a chlorine atomcan be exemplified, of which a fluorine atom is particularly preferred.

Regarding the steric environment at this moiety, it is particularlydesirable that the halogen atom and pyridonecarboxylic acid moiety takecis-configuration on the cyclopropane ring.

So-called enantiomorphic isomers are present due to thecis-2-halogenocyclopropyl moiety alone of R³, and strong antibacterialactivity and high safety have been found in both isomers.

The compound of the present invention shows excellent characteristics byhaving a substituent represented by the following formula at the10-position of the2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylicacid skeleton or at the 7-position of the6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid skeleton.

This substituent exists in the following four optical isomeric forms,due to the asymmetric carbon atom at 3-position of the pyrrolidine ringand the asymmetric carbon atom at 1-position of thecycloalkyl-substituted aminomethyl substituent.

Among these, the present inventors considered that the structure of thefollowing formula was more desirable.

That is, it was revealed that, when the 10-position of the2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylicacid skeleton or the 7-position of the6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid skeleton has the substituent represented by the above formula, thecompound of the present invention shows strong antibacterial activityupon Gram-negative bacteria and Gram-positive bacteria and also showsexcellent safety and good pharmacokinetics, such as negativness of themicronuclear test (very weak micronucleus induction toxicity) which wasnot expected before the present invention.

Where the compound of formula (I) of the present invention has astructure allowing the existence of diastereomers, it is desirable toadminister a compound comprising a pure diastereomer in administrationto humans or animals. The term “comprising a pure diastereomer” as usedherein means not only a case in which it is completely free from theother diastereomer(s) but also a case in which it is in a chemicallypure degree. In other words, it is interpretable that the otherdiastereomer(s) may be present in such a degree that it does not exertinfluences upon physical constants and physiological activities of thecompound.

Also, the term “stereochemically pure” as used herein means a compoundconsisting of one of its stereoiomers when the compound has a pluralityof isomers due to asymmetric carbon atom (s) contained therein. The term“pure” in this case can also be considered in the same manner asdescribed above.

The compound of the present invention may be used either in its freeform or as an acid addition salt or a salt of its carboxyl group.Examples of the acid addition salt include hydrochloride, sulfate,nitrate, hydrobromide, hydroiodide, phosphate and the like inorganicacid salts, or methanesulfonate, benzenesulfonate, toluenesulfonate(sulfonate), acetate, citrate, maleate, fumarate, lactate (carboxylate)and the like organic acid salts.

The salt of carboxyl group may be either inorganic or organic salt, andits illustrative examples include lithium salt, sodium salt, potassiumsalt and the like alkali metal salts, magnesium salt, calcium salt andthe like alkaline earth metal salts, ammonium salt, or triethylaminesalt, N-methylglucamine salt, tris-(hydroxylmethyl)aminomethane salt andthe like.

Also, these free form, acid addition salts and salts of carboxyl groupof the compound may be present as hydrates.

When the compound of the present invention is used for antibacterialpurpose, it is desirable to use a carboxylic acid compound in which thegroup Y is a hydrogen atom, while a quinolone derivative whosecarboxylic acid moiety is an ester is useful as a synthesis intermediateor a prodrug. For example, alkyl esters, benzyl esters, alkoxyalkylesters, phenylalkyl esters and phenyl esters are useful as synthesisintermediates.

Also, the ester to be used as a prodrug is an ester which is susceptibleto an in vivo cleavage to form a free carboxylic acid, and itsillustrative examples include acetoxymethyl ester, pivaloyloxymethylester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester,5-indanyl ester, phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethylester, and oxoalkyl ester such as 3-acetoxy-2-oxobutyl eater.

The compound of the present invention represented by the formula (I) canbe produced by various method, and, in a preferred example of thesemethods, it can be produced for example by reacting a compoundrepresented by formula (III):

[wherein X³ is a substituent which functions as a leaving group, such asa fluorine atom, a chlorine atom, a bromine atom, a substituted orunsubstituted phenylsulfonyl group or a substituted or unsubstitutedalkylsulfonyl group having 1 to 3 carbon atoms,

Y¹ is the Y defined in the formula (I) or a boron-containing grouprepresented by formula (IV):

—B(Y ¹¹)Y ¹²  (IV)

(wherein Y¹¹ and Y¹² each represents a fluorine atom or analkylcarbonyloxy group having 2 to 4 carbon atoms), and R³, R⁴, R⁵, A¹and X¹ are as defined in the formula (I)] with a compound represented byformula (V):

[wherein R¹¹ and R²¹ each independently represents a hydrogen atom, analkyl group having 1 to 6 carbon atoms or a protective group for aminogroup, in which the alkyl group may have a substituent selected from thegroup consisting of a hydroxyl group, a halogen atom, an alkylthio grouphaving 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbonatoms, and n is as defined in the formula (I)] or an addition saltthereof (examples of the acid addition salt include hydrochloride,sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the likeinorganic acid salts, or methanesulfonate, benzenesulfonate,toluenesulfonate (sulfonate), acetate, citrate, maleate, fumarate,lactate (carboxylate) and the like organic acid salts).

The reaction can be carried out using or without using a solvent. Thesolvent to be used in the reaction may be any solvent which is inertunder the reaction conditions, and its illustrative examples includedimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform,dimethylformamide, dimethylacetamide, N-methylpyrrolidone,tetrahydrofuran, water and 3-methoxybutanol or a mixture thereof.

Preferably, the reaction may be carried out in the presence of an acidacceptor such as an inorganic base (e.g., an alkali metal or alkalineearth metal carbonate or bicarbonate) or an organic base (e.g.,triethylamine, pyridine, 1,8-diazabicycloundecene).

The reaction can be carried out at a temperature of from roomtemperature to 200° C., preferably from 25 to 150° C. The reaction iscarried out for a period of from 30 minutes to 48 hours and completesgenerally after about 30 minutes to 2 hours.

When the amino group is protected, examples of the protective group foramino group include those which are generally used in this field, suchas tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the likealkoxycarbonyl groups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl,para-nitrobenzyloxycarbonyl and the like aralkyloxycarbonyl groups,acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl,benzoyl and the like acyl groups, tert-butyl, benzyl, para-nitrobenzyl,para-methoxybenzyl, triphenylmethyl and the like alkyl or aralkylgroups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl,2,2,2-trichloroethoxymethyl and the like ethers and trimethylsilyl,isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl,tert-butyldiphenylsilyl and the like substituted silyl groups.

When Y and Y¹ are an alkyl group having 1 to 6 carbon atoms, analkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl groupcomposed of an alkylene group having 1 to 6 carbon atoms and phenylgroup, the compound of interest can be converted into its correspondingcarboxylic acid compound by treating it under an acidic or basiccondition which is generally employed for the hydrolysis of carboxylicacid esters.

When Y¹ is a structure of the formula (IV), its conversion intocorresponding carboxylic acid compound can be effected by allowing thecompound (III) to react with the compound (V) and then treating it underan acidic or basic condition.

In addition, when de-protection is necessary, the compound of interestrepresented by the formula (I) can be obtained by removing theprotective group under suitable conditions for the protective group.

The compound of formula (V) can be produced by various methods, and,though not particularly limited, it can be synthesized by a method shownin the reference examples as a preferred example in which synthesis of3-[1-(S)-amino-1-cycloalkyl]methylpyrrolidine is described as asynthetic example of 3-[1-amino-1-cycloalkyl]methylpyrrolidine, so thatthe compound of formula (V) can be produced in accordance with thismethod using a known optically active cycloalkyl-substituted glycinederivative.

The cis-2-fluorocyclopropylamine comprised of a pure isomer, which isdesirable for the synthesis of the compound of formula (I) comprised ofa pure isomer, can be synthesized for example by the method described inJP-A-2-231475 (the term “JP-A” as used herein means an “unexaminedpublished Japanese patent application”). Synthesis of the compound offormula (I) comprised of a pure isomer can be carried out using the thusobtained optically active cis-2-fluorocyclopropylamine derivative as thematerial, in accordance with the method described for example inJP-A-2-231475.

The following can be cited as illustrative examples of the compound ofthe present invention.

10-[3-(R)-[1-(S)-Amino-1-cyclopropyl]methylpyrrolidine-1-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylicacid;

8-amino-10-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidine-1-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxylicacid;

7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8methoxy-4-oxoquinoline-3-carboxylicacid;

5-amino-7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid;

7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid;

5-amino-7-[3-(R)-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid; and

5-amino-7-[3-(R)-[1-(S)-cyclopropyl-1-N-methylamino]methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

These compounds have the following structures.

Since the compound of the present invention has strong antibacterialactions, it can be used as drugs for use in human bodies, animals andfishes or as preservatives of agricultural chemicals and food.

When the compound of the present invention is used as a drug for humanbodies, its dose is within the range of from 50 mg to 1 g, preferablyfrom 100 mg to 300 mg, per day for an adult.

Its dose as a drug for use in animals varies depending on the purpose ofits administration (treatment or prevention), kind and size of eachanimal to be treated and kind and degree of each infected pathogenicbacterium, but the dose may be within the range of generally from 1 mgto 200 mg, preferably from 5 mg to 100 mg, per 1 kg body weight per day.

The daily dose may be used once a day or by dividing it into 2 to 4doses per day. As occasion demands, the daily dose may exceed theaforementioned range.

Since the compound of the present invention is active against a broadrange of microorganisms causing various infectious diseases andeffective to treat, prevent or alleviate diseases induced by thesepathogens.

Illustrative examples of bacteria and bacterioid microorganisms on whichthe compound of the present invention is effective include those whichbelong to the genus Staphylococcus, Streptococcus pyogens, hemolyticstreptococci, enterococcus, pneumococcus, those which belong to thegenus Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, thosewhich belong to the genera Citrobacter and Shigella, Klebsiellapneumoniae, those which belong to the genera Enterobacter, Serratia andProteus, Pseudomonas aeruginosa, Haemophilus influenzae, those whichbelong to the genera Acinetobacter and Campylobacter and Chlamydiatrachomatis. Illustrative examples of diseases which are induced bythese pathogens include folliculitis, furuncle, carbuncle, erysipelas,phlegmon, lymphangitis/lymphadenitis, felon, subcutaneous abscess,hidradenitis, acne conglobata, infectious atheroma, perirectal abscess,mastitis, superficial secondary infections after injury, burn injury,operative wound and the like, pharyngitis, acute bronchitis, tonsilitis,chronic bronchitis, bronchiectasis, diffuse bronchiolitis, secondaryinfection of chronic respiratory disease, pneumonia, pyelonephritis,cystitis, prostatitis, epididymitis, gonococcal urethritis, nonspecificurethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis,uterine adnexitis, intrauterine infection, bartholinitis, blepharitis,hordeolum, dacryocystitis, tarsadenitis, corneal ulcer, octitis media,sinusitis, periodentitis, pericoronitis, jaw infection, peritonitis,endocarditis, sepsis, meningitis and skin infection.

The compound of the present invention is also effective against variousmicroorganisms causing infectious diseases in animals, such as thosewhich belong to the genera Escherichia, Salmonella, Pasteurella,Haemaphilus, Bordetella, Staphylococcus and Mycoplasma. Illustrativeexamples of such diseases include colibacillosis, pullorum disease,avian paratyphoid, avian cholera, infectious coryza, staphylococcosis,mycoplasma infection and the like in the case of birds; colibacillosis,salmonellosis, pasteurellosis, haemophilus infection, atrophic rhinitis,exudative epidermis, mycoplasma infection and the like in the case ofpigs; colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasmainfection, bovine pleuropneumonia, bovine mastitis and the like in thecase of cattle; colisepsis, salmonella infection, hemorrhagic sepsis,uterine empyema, cystitis and the like in the case of dogs; andexudative pleurisy, cystitis, chronic rhinitis, haemophilus infection,kitten diarrhea, mycoplasma infection and the like in the case of cats.

The antibacterial preparation which comprises the compound of thepresent invention can be prepared by selecting an appropriatepreparation depending on each administration method and employinggenerally used various preparation method. Regarding the dosage form ofthe antibacterial preparation which uses the compound of the presentinvention as its principal agent, tablets, powders, granules, capsules,solutions, syrups, elixirs, oily or aqueous suspensions and the like canbe exemplified as oral preparations.

Regarding injections, a stabilizing agent, an antiseptic agent and asolubilizing agent may be used in the preparation, or a solution whichmay contain these auxiliary agents may be contained in a container andmade into a solid preparation by freeze-drying or the like means to bere-dissolved when used. In addition, a single dose may be contained in asingle container or multiple doses may be contained in the samecontainer.

Also, solutions, suspensions, emulsions, ointments, gels, creams,lotions, sprays and the like can be exemplified as preparations forexternal use.

Solid preparations may contain pharmaceutically acceptable additivestogether with the active compound and can be prepared for example bymixing the compound with additives optionally selected from fillers,extenders, binders, disintegrators, solubilization enhancing agents,moistening agents, lubricating agents and the like. As liquidpreparations, solutions, suspensions, emulsions and the like can beexemplified, which may contain a suspending agent, an emulsifying agentand the like as additives.

Examples of the method for administering the compound of the presentinvention to animals include a method in which it is orally administereddirectly or by mixing it with feed, a method in which it is made into asolution and then orally administered directly or by mixing it withdrinking water or feed and a method in which it is administered byinjection.

Regarding the pharmaceutical preparations for use in the administrationof the compound of the present invention to animals, it can be madeoptionally into powders, fine subtilaes, soluble powders, syrups,solutions or injections making use of the techniques generally used inthis field.

Formulation examples of the pharmaceutical preparations are shown below.

Formulation Example 1 (Capsules)

Compound of Inventive Example 2 100.0 mg Corn starch 23.0 mg CMC calcium22.5 mg Hydroxymethyl cellulose 3.0 mg Magnesium stearate 1.5 mg Total150.0 mg

Formulation Example 2 (Solutions)

Compound of Inventive Example 2 1-10 g Acetic acid or sodium hydroxide0.5-2 g Ethyl para-hydroxybenzoate 0.1 g Purified water 88.9-98.4 gTotal 100 g

Formulation Example 3 (Powders for Mixing With Feed)

Compound of Inventive Example 2 1-10 g Corn starch 98.5-89.5 g Lightanhydrous silicic acid 0.5 g Total 100 g

BEST MODE FOR CARRYING OUT INVENTION

Examples of the present invention are given below by way of illustrationand not by way of limitation.

REFERENCE EXAMPLE 1 1-Cyclopropyl-2-propen-1-one

Under a stream of nitrogen, cyclopropylmethyl ketone (6.33 g, 75.2 mmol)was dissolved in anhydrous tetrahydrofuran (75 ml). While stirring underice-cooling, to this was added dropwise a solution which had beenprepared by dissolving N-methylanilinium trifluoroacetate (25.0 g, 113.mol) in 37% formaldehyde aqueous solution (10.2 ml) under ice-cooling.After the dropwise addition, the reaction solution was heated underreflux for 7 hours. After cooling, the reaction solution was mixed withdiethyl ether (100 ml) and stirred, and then the organic layer wasseparated. The aqueous layer was extracted with diethyl ether (50 ml).The organic layers were combined, gradually mixed with saturated sodiumbicarbonate aqueous solution (100 ml) and stirred, and then the organiclayer was separated. The thus separated organic layer was washed withsaturated sodium chloride aqueous solution (100 ml). This was dried overanhydrous magnesium sulfate, filtered and then concentrated to 8.01 gunder a reduced pressure of 150 mmHg, thereby obtaining a yellow oilcontaining the title compound. This product was used in the subsequentreaction without purification.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90-0.96 (2H, m), 1.08-1.13 (2H, m),2.14-2.25 (1H, m), 5.82 (1H, dd, J=10.74, 1.47 Hz), 6.29 (1H, dd,J=17.57, 1.47 Hz), 6.47 (1H, dd, J=17.57, 10.74 Hz)

REFERENCE EXAMPLE 2Cyclopropyl[1-[1-(R)-phenylethyl]pyrrolidin-3-yl]ketone

The product containing 1-cyclopropyl-2-propen-1-one described inReference Example 1 (8.01 g) andN-(normal-butoxymethyl)-N-[1-(R)-phenylethyl]trimethylsilylmethylamine(23.2 g, 79.9 mmol) were dissolved in dry dichloroethane (350 ml) towhich was subsequently added dropwise trifluoroacetic acid (500 μl).After 12 hours of stirring at room temperature, the reaction solutionwas washed with saturated sodium bicarbonate aqueous solution (100 ml)and saturated sodium chloride aqueous solution (100 ml) in that order.This was dried over anhydrous magnesium sulfate, filtered and thenconcentrated under a reduced pressure. The resulting residue was appliedto a flash silica gel chromatography and eluted with n-hexane:ethylacetate=2:1, thereby obtaining 9.08 g (49.6%) of the title compound as acolorless oil. In this connection, this product was obtained as a 1:1diastereomer mixture.

¹H-NMR (400 MHz, CDCl₃) 67 : 0.83-0.88 (2H, m), 0.99-1.02 (2H, m), 1.38(3H×1/2, d, J=2.93 Hz), 1.40 (3H x×1/2, d, J=2.44 Hz), 1.62-1.76 (1H,m), 1.90-2.17 (2H, m), 2.35-2.93 (4H, m), 3.22-3.26 (2H, m), 7.23-7.34(5H, m)

REFERENCE EXAMPLE 33-[1-(tert-Butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine

Cyclopropyl[1-[1-(R)-phenylethyl]pyrrolidin-3-yl] ketone (1.563 g, 7.793mmol) was dissolved in anhydrous methanol (25 ml). To this were addedammonium acetate (5.236 g, 67.93 mmol), sodium cyanoborohydride (435.2mg, 6.925 mmol) and Molecular Sieves 4A powder (1.86 g), and the mixturewas stirred at room temperature for 16 hours under a stream of nitrogen.The reaction solution was filtered through celite, and the solvent wasevaporated under a reduced pressure. The resulting residue was dissolvedin dichloromethane (100 ml), and the solution was washed with saturatedsodium bicarbonate aqueous solution (50 ml) and saturated sodiumchloride aqueous solution (50 ml) in that order, and then dried overanhydrous magnesium sulfate. After filtration, the solvent wasconcentrated under a reduced pressure. The thus obtained residue wasdissolved in dry dichloromethane (25 ml) to which, under ice-cooling,was subsequently added dropwise dichloromethane (5 ml) solution ofdi-tert-butyl bicarbonate (2.225 g, 10.19 mmol). The reaction solutionwas stirred at room temperature for 2 hours and then concentrated undera reduced pressure. The thus obtained residue was applied to a flashsilica gel chromatography and eluted with chloroform:methanol=10:1,thereby obtaining 1.299 g (55.5%) of the title compound as a colorlessoil. In this connection, this product was obtained as a mixture of fouroptical isomers.

¹H-NMR (400 MHz, CDCl₃) 67 : 0.20-0.30, 0.35-0.52, 0.68-0.78 (4H, m),1.36 (3H×1/4, d, J=5.86 Hz), 1.39 (3H×3/4, d, J=5.86 Hz), 1.43 (9H×1/4,s), 1.45 (9H×3/4, s), 1.61-1.74 (1H, m), 2.25-2.76, 2.80-3.07, 3.18-3.26(9H, m), 5.28 (1H, brs), 7.23-7.34 (5H, m)

REFERENCE EXAMPLE 41-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine(F1, F2, F3 and F4)

3-[1-(tert-Butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine(1.234 g, 3.582 mmol) was dissolved in dry dichloromethane (20 ml) towhich, under ice-cooling, was subsequently added dropwise benzylchloroformate (1278 μl, 8.955 mmol). After 8 hours of stirring at roomtemperature, the reaction solution was concentrated under a reducedpressure. The thus obtained residue was applied to a flash silica gelchromatography and eluted with n-hexane:ethyl acetate=2:1, therebyobtaining 959 mg (71.5%) of the title compound as a colorless oil.

Thereafter, this product was subjected to fractional HPLC using a chiralcolumn to isolate and purify four optical isomers F1, F2, F3 and F4.

HPLC fractionation conditions;

Column: CHIRALPAKAD (Daicel Chemical Industries), 2 cm×25 cm

Mobile phase: n-hexane:2-propanol=80:20 (v/v)

Flow rate: 5.0 ml/min

Temperature: room temperature

Detection: UV (254 nm)

Retention time of each optical isomer

F1: 18 minutes; F2: 23 minutes; F3: 26 minutes; F4: 30 minutes

Isomer F1: colorless amorphous, 229 mg (17.0%);

¹H-NMR (400 MHz, CDCl₃) 67 : 0.27-0.32 (2H, m), 0.41-0.45 (1H, m),0.54-0.61 (1H, m), 0.72-0.79 (1H, m), 1.43 (9H, s), 1.66-1.78 (1H, m),1.99-2.08 (1H, m), 2.30-2.36 (1H, m), 2.90-3.03 (1H, m), 3.12-3.26 (1H,m), 3.28-3.36 (1H, m), 3.49-3.72 (2H, m), 4.50 (1H, brs), 5.13 (2H, s),7.30-7.37 (5H, m)

Isomer F2: colorless amorphous, 96 mg (7.2%);

¹H-NMR (400 MHz, CDCl₃) δ: 0.29-0.37 (2H, m), 0.40-0.45 (1H, m),0.57-0.62 (1H, m), 0.76-0.79 (1H, m), 1.43 (9H, s), 1.68-1.78 (1H, m),2.04-2.09 (1H, m), 2.36-2.40 (1H, m), 2.95-3.09 (1H, m), 3.16 (1H, t,J=10.74 Hz), 3.31-3.39 (1H, m), 3.54-3.68 (2H, m), 4.47 (1H, brs), 5.13(2H, s), 7.29-7.37 (5H, m)

Isomer F3: colorless amorphous, 140 mg (10.4%);

¹H-NMR (400 MHz, CDCl₃) 67 : 0.27-0.39 (2H, m), 0.41-0.45 (1H, m),0.54-0.62 (1H, m), 0.72-0.80 (1H, m), 1.43 (9H, s), 1.66-1.79 (1H, m),2.04-2.09 (1H, m), 2.37-2.40 (1H, m), 2.95-3.08 (1H, m), 3.16 (1H, t,J=10.74 Hz), 3.32-3.39 (1H, m), 3.54-3.68 (2H, m), 4.48 (1H, brs), 5.13(2H, s), 7.30-7.37 (5H, m)

Isomer F4: colorless amorphous, 296 mg (22.1%);

¹H-NMR (400 MHz, CDCl₃) δ: 0.27-0.33 (2H, m), 0.41-0.45 (1H, m),0.54-0.62 (1H, m), 0.72-0.80 (1H, m), 1.43 (9H, s), 1.68-1.78 (1H, m),1.99-2.09 (1H, m), 2.29-2.39 (1H, m), 2.90-3.03 (1H, m), 3.12-3.26 (1H,m), 3.28-3.37 (1H, m), 3.49-3.73 (2H, m), 4.50 (1H, brs), 5.13 (2H, s),7.30-7.37 (5H, m)

Based on the results of the analysis of these ¹H-NMR data, it wasconfirmed that each combination of F1 and F4 and F2 and F3 has theenantiomorphic relation.

INVENTIVE EXAMPLE 15-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (the substituent at the 7-position is originated from F1)

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine(originated from F1 of Reference Example 4; 185 mg, 0.494 mmol) wasdissolved in anhydrous methanol (30 ml), and the solution was mixed with10% palladium on carbon catalyst (water content 50%, 200 mg) and stirredat room temperature for 1 hour in an atmosphere of hydrogen underatmospheric pressure. After filtration of the reaction solution throughcelite, the resulting filtrate was concentrated under a reducedpressure. The thus obtained residue and triethylamine (2 ml) were addedto dry acetonitrile (10 ml), and the mixture was further mixed with5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (130 mg, 0.412 mmol) and heated under reflux for 16 hours. Aftercooling of the reaction solution, the thus precipitated crystals werecollected by filtration, washed with acetonitrile, mixed withconcentrated hydrochloric acid (10 ml) under ice-cooling and thenstirred at room temperature for 5 minutes. This was mixed with distilledwater (15 ml), and the thus obtained acidic aqueous solution was washedwith dichloromethane (20 ml×2), adjusted to pH 11 with sodium hydroxideaqueous solution under ice-cooling and then washed with chloroform (10ml). The resulting basic aqueous solution was adjusted to pH 7.4 with 1N hydrochloric acid and extracted with chloroform (100 ml×4). Afterdrying over anhydrous sodium sulfate, the solvent was evaporated under areduced pressure. Thereafter, the resulting residue was purified byrecrystallizing from ethanol-28% aqueous ammonia and then dried under areduced pressure, thereby obtaining 160 mg (88.9%) of the title compoundas yellow needle crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ: 0.11-0.18 (2H, m), 0.39 (2H, d, J=7.81Hz), 0.57-0.67 (1H, m), 1.24-1.35 (1H, m), 1.43-1.61 (3H, m), 1.93-2.06(2H, m), 3.20-3.26 (1H, m), 3.37-3.49 (2H, m), 3.59-3.72 (2H, m), 4.97(1H, dm, J=64.16 Hz), 8.21 (1H, s)

Melting point: 185-193° C.

Elemental analysis data for C₂₁H₂₃F₃N₄O₃.0.25H₂O Calcd.: C, 57.20; H,5.37; N, 12.71. Found: C, 57.16; H, 5.39; N, 12.88.

INVENTIVE EXAMPLE 25-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (the substituent at the 7-position is originated from F2)

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine(originated from F2 of Reference Example 4; 75 mg, 0.200 mmol) wasdissolved in anhydrous methanol (15 ml), and the solution was mixed with10% palladium on carbon catalyst (water content 50%, 100 mg) and stirredat room temperature for 1 hour in an atmosphere of hydrogen underatmospheric pressure. After filtration of the reaction solution throughcelite, the resulting filtrate was concentrated under a reducedpressure. The thus obtained residue and triethylamine (1 ml) were addedto dry acetonitrile (5 ml), and the mixture was further mixed with5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (53 mg, 0.167 mmol) and heated under reflux for 12 hours. Aftercooling of the reaction solution, the thus precipitated crystals werecollected by filtration, washed with acetonitrile, mixed withconcentrated hydrochloric acid (5 ml) under ice-cooling and then stirredat room temperature for 5 minutes. This was mixed with distilled water(10 ml), and the thus obtained acidic aqueous solution was washed withdichloromethane (15 ml×2), adjusted to pH 11 with sodium hydroxideaqueous solution under ice-cooling and then washed with chloroform (10ml). The resulting basic aqueous solution was adjusted to pH 7.4 with 1N hydrochloric acid and extracted with chloroform (80 ml×3). Afterdrying over anhydrous sodium sulfate, the solvent was evaporated under areduced pressure. Thereafter, the resulting residue was purified byrecrystallizing from ethanol-28% aqueous ammonia and then dried under areduced pressure, thereby obtaining 55 mg (75.5%) of the title compoundas yellow needle crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ: 0.13-0.19 (1H, m), 0.22-0.30 (1H, m),0.41-0.49 (1H, m), 0.52-0.60 (1H, m), 0.73-0.84 (1H, m), 1.53-1.72 (3H,m), 1.86 (1H, t, J=9.28 Hz), 2.11-2.29 (2H, m), 3.44-3.57 (2H, m),3.62-3.68 (1H, m), 3.72-3.95 (2H, m), 4.96 (1H, dm, J=63.95 Hz), 8.24(1H, s)

Melting point: 190-192° C.

Elemental Analysis data for C₂₁H₂₃F₃N₄O₃.0.25H₂O Calcd.: C, 57.20; H,5.37; N, 12.71. Found: C, 57.27; H, 5.36; N, 12.65.

INVENTIVE EXAMPLE 35-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (the substituent at the 7-position is originated from F3)

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine(originated from F3 of Reference Example 4; 100 mg, 0.267 mmol) wasdissolved in anhydrous methanol (20 ml), and the solution was mixed with10% palladium on carbon catalyst (water content 50%, 100 mg) and stirredat room temperature for 1 hour in an atmosphere of hydrogen underatmospheric pressure. After filtration of the reaction solution throughcelite, the resulting filtrate was concentrated under a reducedpressure. The thus obtained residue and triethylamine (2 ml) were addedto dry acetonitrile (8 ml), and the mixture was further mixed with5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (80 mg, 0.222 mmol) and heated under reflux for 16 hours. Aftercooling of the reaction solution, the thus precipitated crystals werecollected by filtration, washed with acetonitrile, mixed withconcentrated hydrochloric acid (10 ml) under ice-cooling and thenstirred at room temperature for 5 minutes. This was mixed with distilledwater (15 ml), and the thus obtained acidic aqueous solution was washedwith dichloromethane (20 ml×2), adjusted to pH 11 with sodium hydroxideaqueous solution under ice-cooling and then washed with chloroform (20ml). The resulting basic aqueous solution was adjusted to pH 7.4 with 1N hydrochloric acid and extracted with chloroform (80 ml×4). Afterdrying over anhydrous sodium sulfate, the solvent was evaporated under areduced pressure. Thereafter, the resulting residue was purified byrecrystallizing from ethanol-28% aqueous ammonia and then dried under areduced pressure, thereby obtaining 59 mg (60.8%) of the title compoundas yellow needle crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ: 0.12-0.17 (1H, m), 0.21-0.28 (1H, m),0.41-0.48 (1H, m), 0.51-0.60 (1H, m), 0.72-0.82 (1H, m), 1.44-1.53 (3H,m), 1.81 (1H, t, J=8.79 Hz), 2.09-2.28 (2H, m), 3.41-3.47 (1H, m),3.49-3.57 (1H, m), 3.59-3.66 (1H, m), 3.72-3.80 (2H, m), 4.95 (1H, dm,J=65.11 Hz), 8.19 (1H, s)

Melting point: 193-194° C.

Elemental analysis data for C₂₁H₂₃F₃N₄O₃.0.25H₂O Calcd.: C, 57.20; H,5.37; N, 12.71. Found: C, 57.21; H, 5.37; N, 12.70.

INVENTIVE EXAMPLE 45-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (the substituent at the 7-position is originated from F4)

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine(originated from F4 of Reference Example 4; 200 mg, 0.534 mmol) wasdissolved in anhydrous methanol (20 ml), and the solution was mixed with10% palladium on carbon catalyst (water content 50%, 200 mg) and stirredat room temperature for 1 hour in an atmosphere of hydrogen underatmospheric pressure. After filtration of the reaction solution throughcelite, the resulting filtrate was concentrated under a reducedpressure. The thus obtained residue and triethylamine (3 ml) were addedto dry acetonitrile (15 ml), and the mixture was further mixed with5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (141 mg, 0.445 mmol) and heated under reflux for 16 hours. Aftercooling of the reaction solution, the thus precipitated crystals werecollected by filtration, washed with acetonitrile, mixed withconcentrated hydrochloric acid (10 ml) under ice-cooling and thenstirred at room temperature for 5 minutes. This was mixed with distilledwater (20 ml), and the thus obtained acidic aqueous solution was washedwith dichloromethane (20 ml×2), adjusted to pH 11 with sodium hydroxideaqueous solution under ice-cooling and then washed with chloroform (20ml). The resulting basic aqueous solution was adjusted to pH 7.4 with 1N hydrochloric acid and extracted with chloroform (100 ml×4). Afterdrying over anhydrous sodium sulfate, the solvent was evaporated under areduced pressure. Thereafter, the resulting residue was purified byrecrystallizing from ethanol-28% aqueous ammonia and then dried under areduced pressure, thereby obtaining 138 mg (71.1%) of the title compoundas yellow needle crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ: 0.12-0.23 (2H, m), 0.41-0.51 (2H, m),0.70-0.87 (1H, m), 1.46-1.66 (3H, m), 1.80-1.88 (1H, m), 2.08-2.30 (2H,m), 3.46-3.60 (2H, m), 3.62-3.69 (1H, m), 3.72-3.82 (2H, m), 4.96 (1H,dm, J=63.89 Hz), 8.19 (1H, s)

Melting point: 188-194° C.

Elemental analysis data for C₂₁H₂₃F₃N₄O₃ Calcd.: C, 57.79; H, 5.31; N,12.84. Found: C, 57.56; H, 5.39; N, 12.88.

REFERENCE EXAMPLE 5 Ethyl4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-oxobutanoate

Malonic acid monoethyl ester (988.4 mg, 7.482 mmol) was dissolved inanhydrous tetrahydrofuran (20 ml), and the solution was mixed withmagnesium ethoxide (488 mg, 3.93 mmol) under ice-cooling and thenstirred at room temperature for 2 hours. The reaction solution wasconcentrated to dryness under a reduced pressure, and the thus obtainedpowder was dissolved in anhydrous tetrahydrofuran (30 ml).

L-N-Benzyloxycarbonyl-cyclopropylglycine (1.332 g, 5.334 mmol) wasdissolved in anhydrous tetrahydrofuran (20 ml), and the solution wasmixed with N,N′-carbonyldiimidazole (910 mg, 5.61 mmol) underice-cooling and then stirred at room temperature for 2 hours. Underice-cooling, the aforementioned tetrahydrofuran solution previouslyprepared was added dropwise to the just prepared solution, and themixture was stirred at room temperature for 16 hours.

The reaction solution was concentrated under a reduced pressure, and theresulting residue was mixed with toluene (60 ml) and 10% citric acidaqueous solution (50 ml) and stirred at room temperature for 5 minutes.The organic layer was separated and the aqueous layer was extracted withtoluene (20 ml×2). The organic layers were combined, washed with water(50 ml) and saturated sodium chloride aqueous solution (50 ml) in thatorder, and then dried over anhydrous magnesium sulfate. Afterfiltration, the solvent was evaporated under a reduced pressure and theresulting residue was applied to a flash silica gel chromatography andeluted with n-hexane:ethyl acetate=2:1, thereby obtaining 1.527 g(89.4%) of the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.53-0.61 (3H, m), 0.67-0.77 (1H, m),0.90-1.01 (1H, m), 1.27 (3H, t, J=7.33 Hz), 3.65 (2H, s), 3.89-3.93 (1H,m), 4.20 (2H, q, J=7.33 Hz), 5.10 (2H, s), 5.47 (1H, brs), 7.31-7.35(5H, m)

REFERENCE EXAMPLE 6 Ethyl4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-hydroxybutanoate

Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-oxobutanoate (1.526g, 4.778 mmol) was dissolved in anhydrous ethanol (15 ml), and thesolution was mixed with sodium borohydride (94.6 mg, 2.50 mmol)underice-cooling and stirred at the same temperature for 1 hour. Underice-cooling, the reaction solution was mixed with water (20 ml) and thenethanol was evaporated under a reduced pressure. The thus obtainedresidue was mixed with chloroform (50 ml) and stirred, and then the thusseparated chloroform layer was washed with saturated sodium chlorideaqueous solution (30 ml) and dried over anhydrous magnesium sulfate.After filtration, the solvent was evaporated to dryness under a reducedpressure, thereby obtaining 1.509 g (98.3%) of the title compound as acolorless oil. This product was used in the subsequent reaction withoutpurification.

¹H-NMR (400 MHz, CDCl₃) δ: 0.24-0.67 (4H, m), 0.96-1.06 and 1.08-1.16(total 1 H, m for each), 1.27 (3H, t, J=7.32 Hz), 2.45-2.58 (1H, m),2.66-2.73 (1H, m), 2.84-3.01 (1H, m), 3.33 (1H, brs), 4.17 (2H, q,J=7.32 Hz), 5.09 (2H, s), 5.18 and 5.28 (total 1H, br-s for each),7.30-7.37 (5H, m)

REFERENCE EXAMPLE 7 Ethyl4-(S)-benzyloxycarbonylamino-4-cyclopropyl-2-butenoate

Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-hydroxybutanoate(1.488 g, 4.630 mmol) was dissolved in dry dichloromethane (50 ml) andstirred at -15° C. while adding triethylamine (1,291 μl, 9.260 mmol),and then methanesulfonyl chloride (449 μl, 5.80 mmol) was added dropwisethereto and the mixture was stirred at the same temperature for 1 hour.1,8-Diazabicyclo[5.4.0]-7-undecene (1,486 μl, 1.955 mmol) was addeddropwise to the reaction solution, and the mixture was gradually warmedup to room temperature and then stirred for 15 hours. The reactionsolution was washed with 10% citric acid aqueous solution (50 ml), andthe organic layer was separated and then the aqueous layer was extractedwith chloroform (30 ml). The organic layers were combined, washed withwater (50 ml) and saturated sodium chloride aqueous solution (50 ml) inthat order, and then dried over anhydrous magnesium sulfate. Afterfiltration, the solvent was evaporated under a reduced pressure, and thethus obtained residue was applied to a flash silica gel chromatographyand eluted with n-hexane:ethyl acetate=4:1, thereby obtaining 1.174 g(87.2%) of the title compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.31-0.37 (1H, m), 0.39-0.48 (1H, m),0.52-0.65 (1H, m), 0.86-0.95 (1H, m), 1.29 (3H, t, J=7.33 Hz), 3.73 (1H,brs), 4.20 (2H, q, J=7.33 Hz), 4.92 (1H, brs), 5.11 (2H, s), 5.97 (1H,d, J=15.63 Hz), 6.91 (1H, dd, J=15.63, 5.37 Hz), 7.31-7.36 (5H, m)

REFERENCE EXAMPLE 8 Ethyl4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-nitromethylbutanoate

Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-2-butenoate wasdissolved in dry nitromethane (15 ml), and the solution was mixed with1,1,3,3-tetramethylguanidine (133 μl, 1.05 mol) and stirred at roomtemperature for 17 hours. The reaction solution was concentrated under areduced pressure, the resulting residue was dissolved in chloroform (50ml), and the solution was washed with 10% citric acid aqueous solution(50 ml) and saturated sodium chloride aqueous solution (50 ml) in thatorder, and then dried over anhydrous magnesium sulfate, therebyobtaining 1.207 g (96.1%) of the title compound as a yellow oil. Thisproduct (diastereomer mixture) was used in the subsequent reactionwithout purification.

¹H-NMR (400 MHz, CDCl₃) δ: 0.31-0.45 (1H, m), 0.48-0.56 (1H, m),0.61-0.70 (1H, m), 0.82-0.92 (1H, m), 1.26 (3H, t, J=7.33 Hz), 2.49 (d,J=7.32 Hz), 2.53 (d, J=6.34 Hz), 2.67 (d, J=5.72 Hz), 2.71 (d, J=5.86Hz), (2.49, 2.53, 2.67, 2.67, total 1 H), 3.00 (1H, q, J=6.34 Hz), 3.13(1H, q, J=7.32 Hz), 4.15 (2H, q, J=7.33 Hz), 4.57 and 4.59 (total 2 H,d, J=7.33 Hz), 4.86 (1H, br-s), 5.10 (2H, s), 7.31-7.36 (5H, m)

REFERENCE EXAMPLE 94-(1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidin-2-one(isomer A)

Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-nitromethylbutanoate(16.4 g, 41.0 mmol) was dissolved in ethanol (500 ml), and the solutionwas mixed with 10% palladium on carbon catalyst (water content 50%, 16g) and subjected to 5 hours of catalytic hydrogenation at roomtemperature. After removal of the catalyst by celite filtration, theresulting filtrate was heated under reflux for 6 hours. The solvent wasevaporated under a reduced pressure, the resulting residue was dissolvedin dry dichloranethane, the resulting solution was mixed withtriethylamine (8.24 ml, 59.1 mmol) and then with di-tert-butylbicarbonate (11.32 ml, 49.2 mmol), and then the mixture was stirred atroom temperature for 6 hours. After concentration of the reactionsolution under a reduced pressure, the thus obtained residue was appliedto a flash silica gel chromatography and eluted withchloroform:methanol=95:5, and the thus obtained crystals were purifiedby recrystallizing them from a chloroform-n-hexane system, therebyobtaining 3.34 g (32.0%) of one diastereomer of the title compound as asingle compound (isomer) in the form of white crystals.

¹H-NMR (400 MHz, CDCl₃) δ0.34-0.35 (2H, m), 0.44-0.48 (1H, m), 0.58-0.65(1H, m), 0.72-0.79 (1H, m), 1.44 (9H, s), 2.28 (1H, dd, J=17.09, 9.04Hz), 2.44 (1H, dd, J=17.09, 8.44 Hz), 2.67-2.73 (1H, m), 3.04-3.06 (1H,m), 3.25-3.30 (1H, m), 3.47 (1H, t, J=8.79 Hz), 4.57 (1H, s), 5.84 (1H,s)

REFERENCE EXAMPLE 101-Benzyl-4-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidin-2-one(isomer A)

Under a stream of nitrogen,4-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidin-2-one(3.15 g, 12.4 mmol) was dissolved in dry dimethylformamide (60 ml), andthe solution was mixed with 60% oily sodium hydride (685 mg, 16.1 mmol)under ice-cooling. After 30 minutes of stirring at room temperature,this was mixed with benzyl bromide (2.04 ml, 16.1 mmol) underice-cooling, and the mixture was stirred at room temperature for 13hours. The reaction solution was mixed with water (200 ml) underice-cooling and extracted with ethyl acetate (250 ml). The thusseparated organic layer was washed with water (200 ml×2) and saturatedsodium chloride aqueous solution (150 ml) in that order, and then driedover anhydrous magnesium sulfate. After filtration, the solvent wasapplied to a flash silica gel chromatography and eluted withn-hexane-ethyl acetate=1:1, thereby obtaining 2.74 g (64.2%) of thetitle compound as colorless amorphous.

¹H-NMR (400 MHz, CDCl₃) δ: 0.27-0.28 (2H, m), 0.39-0.43 (1H, m),0.52-0.56 (1H, m), 0.66-0.72 (1H, m), 1.41 (9H, s), 2.39-2.42 (1H, m),2.54-2.62 (2H, m), 3.01 (1H, s), 3.29-3.33 (1H, m), 4.40 (1H, s), 4.33,4.55 (each 1 H, ABq, J=14.4 Hz), 7.23-7.36 (5H, m)

REFERENCE EXAMPLE 111-Benzyl-3-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine(isomer A)

Under a stream of nitrogen,1-benzyl-4-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidin-2-one(2.74 g, 7.95 mmol) was dissolved in dry tetrahydrofuran (70 ml) towhich, under ice-cooling, was subsequently added dropwise aborane-tetrahydrofuran complex (1.0 N tetrahydrofuran solution; 47.7 ml,47.7 mol). After completion of the dropwise addition, and the mixturewas stirred at room temperature for 16 hours. The reaction solution wasconcentrated under a reduced pressure, mixed with a solution ofethanol:water=10:1 (130 ml) and triethylamine (20 ml), and then heatedunder reflux for 4 hours. The reaction solution was concentrated under areduced pressure and mixed with chloroform (100 ml), and the thusseparated organic layer was washed with water (100 ml) and saturatedsodium chloride aqueous solution (50 ml) in that order, and then driedover anhydrous sodium sulfate. After filtration, the solvent wasevaporated under a reduced pressure, and the thus obtained residue wasapplied to a flash silica gel chromatography and eluted withchloroform:methanol=95:5, thereby obtaining 2.63 g (100%) of the titlecompound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ0.19-0.23 (1H, m), 0.35-0.44 (3H, m), 0.73-0.76(1H, m), 1.44 (9H, s), 1.60-1.66 (1H, m), 1.94-2.00 (1H, m), 2.36-2.42(2H, m), 2.51-2.66 (3H, m), 2.95-3.02 (1H, m), 3.52, 3.67 (each 1 H,ABq, J=12.9 Hz), 4.58 (1H, s), 7.24-7.34 (5H, m)

REFERENCE EXAMPLE 121-Benzyloxycarbonyl-3-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine(isomer A=isomer F3 of Reference Example 3)

1-Benzyl-3-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine(isomer A; 238 mg, 0.720 mmol) was dissolved in dry dichloromethane (10ml) to which was subsequently added dropwise benzyl chloroformate (3094μl, 2.16 mmol) under ice-cooling. After 8 hours of stirring at roomtemperature, the reaction solution was concentrated under a reducedpressure. The resulting residue was applied to a flash silica gelchromatography and eluted with n-hexane:ethyl acetate=2:1, therebyobtaining 197 mg (73.1%) of the title compound as colorless amorphous.

The Rf value of TLC (thin layer chromatography, development withn-hexane:ethyl acetate=1:1) and ¹H-NMR data (shown below) of thisproduct coincided with those of the isomer F3 described in ReferenceExample 4. In addition, when this product was checked by HPLC analysisusing a chiral column, its HPLC retention time coincided with theretention time of the optical isomer F3 described in reference Example4. In consequence, it was confirmed that this product (isomer A) is theoptical isomer F3 described in Reference Example 4.

¹H-NMR (400 MHz, CDCl₃) δ: 0.28-0.40 (2H, m), 0.41-0.45 (1H, m),0.53-0.63 (1H, m), 0.72-0.81 (1H, m), 1.43 (9H, s), 1.67-1.79 (1H, m),2.03-2.09 (1H, m), 2.37-2.40 (1H, m), 2.95-3.08 (1H, m), 3.16 (1H, t,J=10.74 Hz), 3.32-3.39 (1H, m), 3.54-3.69 (2H, m), 4.48 (1H, brs), 5.13(2H, s), 7.31-7.37 (5H, m)

HPLC analysis conditions;

Column: CHIRALPAKAD (Daicel Chemical Industries), 0.46 cm×25 cm

Mobile phase: n-hexane:2-propanol=80:20 (v/v)

Flow rate: 1.0 ml/min

Temperature: room temperature

Detection: UV (254 nm)

Retention time of isomer A (F3): 8.16 minutes

Optical purity: 99% e.e.

REFERENCE EXAMPLE 133-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine(isomer A: F3)

1-Benzyl-3-[1-(S)-tert-butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine(isomer A; 744 mg, 2.25 mmol) was dissolved in dry ethanol (30 ml), andthe solution was mixed with 10% palladium on carbon catalyst (watercontent 50%; 750 mg) and stirred at 45° C. (external temperature) for 1hour in an atmosphere of hydrogen under atmospheric pressure. Thereaction solution was filtered through celite, and the resultingfiltrate was concentrated under a reduced pressure, thereby obtaining542 mg (quantitative) of the title compound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ: 0.27-0.42 (2H, m), 0.53-0.57 (1H, m),0.74-0.81 (1H, m), 1.43 (9H, s), 1.55-1.60 (1H, m), 1.89-1.95 (1H, m),2.23-2.26 (3H, m), 2.73-2.77 (1H, m), 2.85-2.90 (1H, m), 2.95-3.01 (2H,m)

INVENTIVE EXAMPLE 55-Amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (the substituent at the 7-position is originated from isomer A, F3)

3-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine(isomer A: F3; 541 mg, 2.25 mmol) and triethylamine (6 ml) were added todry acetonitrile (30 ml), and the mixture was further mixed with5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (548 mg, 1.73 mmol) and heated under reflux for 15 hours. Aftercooling of the reaction solution, the thus precipitated crystals werecollected by filtration, washed with acetonitrile, mixed withconcentrated hydrochloric acid (15 ml) under ice-cooling and thenstirred at room temperature for 5 minutes. This was mixed with distilledwater (15 ml), and the thus obtained acidic aqueous solution was washedwith dichloromethane (20 ml×3), adjusted to pH 11 with sodium hydroxideaqueous solution under ice-cooling and then washed with chloroform (30ml). The resulting basic aqueous solution was adjusted to pH 7.4 with 1N hydrochloric acid and extracted with chloroform (100 ml×5). Afterdrying over anhydrous sodium sulfate, the solvent was evaporated under areduced pressure. Thereafter, the resulting residue was purified byrecrystallizing from an ethanol-28% aqueous ammonia and then dried undera reduced pressure, thereby obtaining 569 mg (75.3%) of the titlecompound as yellow needle crystals.

The Rf value of TLC (thin layer chromatography, developed with underlayer chloroform:methanol:water=7:3:1) and ¹H-NMR data (shown below) ofthis product coincided with the data described in Inventive Example 3.

¹H-NMR (400 MHz, 0.1 N NaOD) δ0.13-0.17 (1H, m), 0.21-0.29 (1H, m),0.41-0.48 (1H, m), 0.51-0.61 (1H, m), 0.73-0.82 (1H, m), 1.43-1.53 (3H,m), 1.81 (1H, t, J=8.79 Hz), 2.10-2.27 (2H, m), 3.41-3.47 (1H, m),3.49-3.58 (1H, m), 3.59-3.66 (1H, m), 3.73-3.81 (2H, m), 4.95 (1H, dm,J=65.11 Hz), 8.19 (1H, s)

Melting point: 192.5-194.5° C.

Elemental analysis data for C₂₁H₂₃F₃N₄O₃.0.25H₂O Calcd.: C, 57.20; H,5.37; N, 12.71. Found: C, 57.18; H, 5.39; N, 12.78.

Specific rotation: [α]_(D) ²⁰=146.1° (c 0.32, 0.1 N NaOH)

INVENTIVE EXAMPLE 67-[3-[1-(S)-Amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid (the substituent at the 7position is originated from isomer A, F3)

4-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine(isomer A: F3; 240 mg, 1.00 mmol) and triethylamine (0.279 ml, 2.00mmol) were added to dry dimethyl sulfoxide (1.5 ml). To this was furtheradded6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid-BF₂ chelate (328 mg, 0.909 mmol), and the mixture was stirred atroom temperature for 17 hours and then at 35° C. for 4 hours. Afterconcentration of the reaction solution under a reduced pressure, theresulting residue was mixed with water, and the thus precipitated solidwas collected by filtration and washed with water. The thus obtainedsolid was suspended in a solution of ethanol:water=10:1, and thesuspension was mixed with triethylamine (2 ml) and heated under refluxfor 3 hours. After cooling, the reaction solution was concentrated undera reduced pressure, and the resulting residue was dissolved inchloroform (100 ml). The organic layer was washed with 10% citric acidaqueous solution (50 ml) and then dried over anhydrous sodium sulfate.After filtration, the resulting filtrate was concentrated under areduced pressure, concentrated hydrochloric acid (5 ml) was addeddropwise to the thus obtained residue under ice-cooling and then themixture was stirred at room temperature for 30 minutes. The reactionsolution was mixed with 1 N hydrochloric acid (5 ml), the thus obtainedyellow acidic aqueous solution was washed with chloroform (50 ml×5) andadjusted to pH 12.0 with sodium hydroxide aqueous solution, and then theinsoluble material was removed by filtration. The resulting basicaqueous solution was adjusted to pH 7.4 with 1 N hydrochloric acid andextracted with chloroform (100 ml×4). After drying over anhydrous sodiumsulfate, the solvent was evaporated under a reduced pressure.Thereafter, the resulting residue was purified by recrystallizing fromethanol and then dried under a reduced pressure, thereby obtaining 285mg (67.3%) of the title compound as yellow crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ0.01-0.05 (1H, m), 0.29-0.32 (1H, m),0.39-0.40 (1H, m), 0.64-0.66 (1H, m), 1.15-1.22 (1H, m), 1.33-1.40 (1H,m), 1.43-1.54 (1H, m), 1.73-1.77 (1H, m), 1.96-1.98 (1H, m), 2.12-2.14(1H, m), 3.28-3.51 (4H, m), 3.42 (3H, s), 3.81-3.86 (1H, m), 4.86 (1H,dm, J=66.6 Hz), 7.49 (1H, d, J=4.56 Hz), 8.25 (1H, d, J=3.42 Hz)

Melting point: 197.5-198.5° C.

Elemental analysis data for C₂₂H₂₅F₂N₃O₄.0.5H₂O.0.5EtOH Calcd.: C,59.50; H, 6.28; N, 9.03. Found: C, 59.50; H, 6.39; N, 8.87.

Specific rotation: [α]_(D) ²⁰=−105.5° (c 0.88, 0.1 N NaOH)

INVENTIVE EXAMPLE 75-Amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (the substituent at the 7-position is originated from isomer A, F3)

4-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine (481mg, 2.00 mmol) and triethylamine (1.5 ml) were added to dry dimethylsulfoxide (2 ml), and the mixture was further mixed with5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (416 mg, 1.33 mmol) and heated under reflux for 72 hours in anatmosphere of nitrogen. After concentration of the reaction solutionunder a reduced pressure, the resulting residue was dissolved inchloroform (100 ml). The organic layer was washed with 10% citric acidaqueous solution (50 ml) and then dried over anhydrous sodium sulfate.After filtration, the resulting filtrate was concentrated under areduced pressure, concentrated hydrochloric acid (5 ml) was addeddropwise to the thus obtained residue under ice-cooling and then themixture was stirred at room temperature for 30 minutes. The reactionsolution was mixed with 1 N hydrochloric acid (5 ml), the thus obtainedyellow acidic aqueous solution was washed with chloroform (50 ml×5) andadjusted to pH 12.0 with sodium hydroxide aqueous solution, and then theinsoluble material was removed by filtration. The resulting basicaqueous solution was adjusted to pH 7.4 with 1 N hydrochloric acid andextracted with chloroform (100 ml×3). After drying over anhydrous sodiumsulfate, the solvent was evaporated under a reduced pressure.Thereafter, the resulting residue was purified by a preparativethin-layer chromatography (developed with under layer ofchloroform:methanol:water=7:3:1), recrystallized from isopropyl alcoholand then dried under a reduced pressure, thereby obtaining 70.0 mg(12.1%) of the title compound as yellow crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ0.01-0.10 (2H, m), 0.27-0.39 (2H, m),0.58-0.64 (1H, m), 0.88-0.97 (1H, m), 1.33-1.45 (2H, m), 1.71-1.74 (1H,m), 1.97-2.10 (2H, m), 2.08 (3H, s), 3.01-3.05 (1H, m), 3.17-3.21 (1H,m), 3.34-3.38 (1H, m), 3.58-3.62 (1H, m), 3.75-3.79 (1H, m), 4.90 (1H,dm), 8.14 (1H, s)

Melting point: 226.7-227.9° C.

Elemental analysis data for C₂₂H₂₆F₂N₄O₃ Calcd.: C, 61.10; H, 6.06; N,12.96. Found: C, 60.84; H, 6.07; N, 12.98. Specific rotation: [α] _(D)²⁰=−329.0° (c 0.20, 0.1 N NaOH)

INVENTIVE EXAMPLE 87-[3-[1-(S)-Amino-1-cyclopropyl)methylpyrrolidin-1-yl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid (the substituent at the 7position is originated from isomer A, F3)

4-[1-(S)-tert-Butoxycarbonylamino-1-cyclopropyl]methylpyrrolidine(isomer A: F3; 330 mg, 1.37 mmol) and triethylamine (0.485 ml, 3.48mmol) were added to 3.0 ml of dry dimethyl sulfoxide, and the mixturewas further mixed with6-fluoro-1-cyclopropyl-1,4-dihydro-8methoxy-4-oxoquinoline-3-carboxylicacid (321 mg, 1.16 mmol) and stirred at 100° C. for 15 hours. Afterconcentration of the reaction solution under a reduced pressure, theresulting residue was dissolved in 100 ml of chloroform. The organiclayer was washed with 50 ml of 10% citric acid aqueous solution and thendried over anhydrous sodium sulfate. After filtration, the resultingfiltrate was concentrated under a reduced pressure, 5 ml of concentratedhydrochloric acid was added dropwise to the thus obtained residue underice-cooling and then the mixture was stirred at room temperature for 30minutes. The reaction solution was mixed with 5 ml of 1 N hydrochloricacid and the thus obtained yellow acidic aqueous solution was washedwith chloroform (50 ml×4), the resulting insoluble material was removedby filtration, and then the solution was adjusted to pH 12.0 with sodiumhydroxide aqueous solution. The resulting basic aqueous solution wasadjusted to pH 7.4 with 1 N hydrochloric acid and extracted withchloroform (100 ml×4). After drying over anhydrous sodium sulfate, thesolvent was evaporated under a reduced pressure. Thereafter, theresulting residue was purified by recrystallizing from ethanol-aqueousammonia and then dried under a reduced pressure, thereby obtaining 230mg (49.9%) of the title compound as yellow crystals.

1H-NMR (400 MHz, 0.1 N NaOD) δ: 0.17-0.18 (1H, m), 0.28-0.29 (1H, m),0.46-0.47 (1H, m), 0.57-0.58 (1H, m), 0.77-0.79 (2H, m), 1.02-1.04 (2H,m), 1.17-1.21 (2H, m), 1.69-1.81 (1H, m), 1.92-1.95 (1H, m), 2.18-2.27(1H, m), 2.35-2.40 (1H, m), 3.33-3.52 (3H, m), 3.52 (3H, s), 4.01-4.11(1H, m), 7.03 (1H, d, J=8.79 Hz), 7.91 (1H, d, J=9.03 Hz), 8.48 (1H, s)

Melting point: 220-221° C.

Elemental analysis data for C₂₂H₂₇N₃O₄.0.5H₂O Calcd.: C, 65.74; H, 6.90;N, 10.45. Found: C, 65.96; H, 6.90; N, 10.36.

REFERENCE EXAMPLE 141-[1-(R)-Phenylethyl]-5-oxopyrrolidine-3-(R)-(N-methyl-N-methoxy)carboxamide

Oxalyl chloride (6.54 ml, 75.0 mmol) and dimethylformamide (3 drops)were added to dichloromethane solution (200 ml) of1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxylic acid (11.7 g,50.0 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for a whole day and night. After evaporation of the solventunder a reduced pressure, toluene (100 ml) was added to the resultingresidue and then the solvent was again evaporated under a reducedpressure. The thus obtained residue was mixed with dichloromethane (200ml) and N,O-ethylhydroxylamine hydrochloride (5.47 g, 55.5 mmol), and tothe mixture, while stirring under ice-cooling, was then added dropwisedichloramethane solution (50 ml) of triethylamine (17.4 ml, 125 mmol) in15 minutes. This was stirred under ice-cooling for 30 minutes and thenat room temperature for 3 hours. The reaction solution was washed with10% citric acid aqueous solution (100 ml), water (100 ml) and saturatedsodium bicarbonate aqueous solution (100 ml) in that order and thendried over anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was applied to a silica gelcolumn chromatography and eluted with a gradient of fromchloroform:methanol=50:1 to 20:1, thereby obtaining 11.3 g (82%) of thetitle compound as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.54 (3H, d, J=6.84 Hz), 2.65 (1H, dd,J=9.77, 7.09 Hz), 2.77 (1H, dd, J=8.79, 7.09 Hz), 3.12-3.18 (1H, m),3.20 (3H, s), 3.37-3.48 (1H, m), 3.55-3.64 (1H, m), 3.65 (3H, s), 5.50(1H, q, J=6.84 Hz), 7.28-7.37 (5H, m)

REFERENCE EXAMPLE 154-(R)-Cyclobutylcarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

In an atmosphere of nitrogen, cyclobutylmagnesium chloride (1 Ntetrahydrofuran solution, 28 ml) prepared from chlorocyclobutane wasadded dropwise to tetrahydrofuran solution (50 ml) of1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-(N-methyl-N-methoxy)carboxamide(1.93 g, 7.00 mmol), and the mixture was stirred at room temperature for30 minutes. The reaction solution was mixed with 1 N hydrochloric acid(50 ml) under ice-cooling and extracted with ethyl acetate (80 ml×2),and the organic layer was washed with saturated sodium chloride aqueoussolution (100 ml) and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the thus obtainedresidue was applied to a silica gel column chromatography and elutedwith n-hexane:ethyl acetate=1:2, thereby obtaining 1.47 g (78%) of thetitle compound as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.53 (3H, d, J=7.33 Hz), 1.78-1.89 (1H, m),1.92-2.06 (1H, m), 2.06-2.31 (4H, m), 2.58-2.65 (2H, m), 3.05 (1H, dd,J=9.28, 8.79 Hz), 3.13-3.21 (1H, m), 3.31 (1H, quint, J=8.30 Hz), 3.53(1H, dd, J=9.28, 6.83 Hz), 5.48 (1H, q, J=7.33 Hz), 7.27-7.37 (5H, m)

REFERENCE EXAMPLE 164-(R)-(1-Cyclobutyl-1-hydroxy)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

Under ice-cooling, sodium borohydride (295 mg) was added to ethanol (40ml) solution of4-(R)-cyclobutylcarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2.12 g,7.80 mol), and the mixture was stirred at the same temperature for 1hour. The reaction solution was mixed with 10% citric acid (50 ml) underice-cooling, ethanol was evaporated under a reduced pressure, the thusobtained residue was extracted with chloroform (80 ml×2), and then theorganic layer was washed with saturated sodium chloride aqueous solution(100 ml) and dried over anhydrous sodium sulfate. The solvent wasevaporated under a reduced pressure, and the thus obtained residue wasapplied to a silica gel column chromatography and eluted with a gradientof from n-hexane:ethyl acetate=1:3 to ethyl acetate, thereby obtaining2.10 g (98%) of the title compound as a light yellow oil (isomermixture).

¹H-NMR (400 MHz, CDCl₃) δ1.50 (3H, d, J=6.83 Hz), 1.68-2.01 (6H, m),2.14-2.45 (3H, m), 2.45-2.56 (1H, m), 2.91-3.05 (1H, m), 3.19-3.31 (1H,m), 3.41-3.49 (1H, m), 5.42-5.49 (1H, m), 7.24-7.36 (5H, m)

REFERENCE EXAMPLE 174-(R)-(1-Azido-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

Under ice-cooling, triethylamine (1.36 ml, 9.80 mmol) and thenmethanesulfonyl chloride (640 μl, 8.30 mmol) were added todichloromethane (35 ml) solution of4-(R)-(1-cyclobutyl-1-hydroxy)methyl-1-[1-(R)-phenylethyl]-2-pyrolidone(2.05 g, 7.50 mmol), and the mixture was stirred at the same temperaturefor 1 hour. The reaction solution was mixed with 10% citric acid (35 ml)under ice-cooling and extracted with chloroform (50 ml×2), and theorganic layer was washed with saturated sodium chloride aqueous solution(150 ml) and then dried over anhydrous sodium sulfate. After evaporationof the solvent under a reduced pressure, the thus obtained residue wasdissolved in N,N′-dimethylformamide (30 ml), and the solution was mixedwith sodium azide (1.46 g, 22.5 mmol) and stirred at 60° C. for 3 hours.After cooling, the reaction solution was mixed with water (150 ml) underice-cooling and extracted with ethyl acetate (150 ml×3), and the organiclayer was washed with saturated sodium chloride aqueous solution (150ml) and then dried over anhydrous sodium sulfate. After evaporation ofthe solvent under a reduced pressure, the thus obtained residue wasapplied to a silica gel column chromatography and eluted withn-hexane:ethyl acetate=3:2, thereby obtaining 898 mg (40%) of a lowpolarity title compound (isomer B1) as a colorless oil and then withn-hexane:ethyl acetate=2:3, thereby obtaining 847 mg (38%) of a highpolarity title compound (isomer B2) as colorless crystals.

Isomer B1

¹H-NMR (400 MHz, CDCl₃) δ: 1.52 (3H, d, J=6.83 Hz), 1.72-2.01 (5H, m),2.07-2.17 (1H, m), 2.26-2.41 (3H, m), 2.45-2.56 (1H, m), 2.98 (1H, dd,J=9.77, 7.81 Hz), 3.14 (1H, dd, J=9.77, 7.32 Hz), 3.32 (1H, dd, J=8.76,3.91 Hz), 5.47 (1H, q, J=6.83 Hz), 7.25-7.35 (5H, m)

Isomer B2

¹H-NMR (400 MHz, CDCl₃) δ: 1.52 (3H, d, J=6.83 Hz), 1.75-2.03 (5H, m),2.03-2.17 (1H, m), 2.19-2.38 (2H, m), 2.40-2.56 (2H, m), 2.99 (1H, dd,J=9.77, 8.30 Hz), 3.14 (1H, dd, J=9.77, 7.32 Hz), 3.30 (1H, dd, J=8.30,6.34 Hz), 5.47 (1H, q, J=6.83 Hz), 7.25-7.35 (5H, m)

REFERENCE EXAMPLE 184-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone(isomer B1)

Ethanol (50 ml) solution of4-(R)-(1-azido-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]-2pyrrolidone(isomer B1) (835 mg, 2.80 mmol) was mixed with 10% palladium on carboncatalyst (water content 53.8%, 850 mg), and 5 hours of catalytichydrogenation was carried out at room temperature in an atmosphere ofhydrogen under atmospheric pressure. The reaction solution was filteredand the solvent was evaporated under a reduced pressure. The resultingresidue was dissolved in dichloromethane (20 ml), and the solution wasmixed with di-tert-butyl bicarbonate (917 mg) and triethylamine (780 1)and stirred at room temperature for 15 hours. The reaction solution wasmixed with chloroform (50 ml) and washed with 10% citric acid (80 ml)and water (80 ml) and then the organic layer was dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure, andthe thus obtained residue was applied to a silica gel columnchromatography and eluted with a gradient of n-hexane:ethyl acetate=3:2to 1:1, thereby obtaining 809 mg (78%) of the title compound as whiteamorphous.

¹H-NMR (400 MHz, CDCl₃) δ1.44 (9H, s), 1.48 (3H, d, J=7.32 Hz),1.66-1.98 (6H, m), 2.17-2.43 (4H, m), 2.94-3.03 (1H, m), 3.09-3.18 (1H,m), 3.59-3.68 (1H, m), 4.46-4.58 (1H, m), 5.46 (1H, q, J=7.32 Hz),7.27-7.35 (5H, m)

REFERENCE EXAMPLE 194-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone(isomer B2)

Ethanol (40 ml) solution of4-(R)-(1-azido-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone(isomer B2) (776 mg, 2.60 mmol) was mixed with 10% palladium on carboncatalyst (water content 53.8%, 800 mg) and 5 hours of catalytichydrogenation was carried out at room temperature in an atmosphere ofhydrogen under atmospheric pressure. The reaction solution was filteredand the solvent was evaporated under a reduced pressure. The thusobtained residue was dissolved in dichloromethane (20 ml), and thesolution was mixed with di-tert-butyl bicarbonate (851 mg) andtriethylamine (725 μl) and stirred at room temperature for 15 hours. Thereaction solution was mixed with chloroform (50 ml) and washed with 10%citric acid (80 ml) and water (80 ml) and then the organic layer wasdried over anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the thus obtained residue was applied to a silicagel column chromatography and eluted with a gradient of n-hexane:ethylacetate=1:1 to 2:3, thereby obtaining 846 mg (87%) of the title compoundas, white amorphous.

¹H-NMR (400 MHz, CDCl₃) δ: 1.43 (9H, s), 1.50 (3H, d, J=7.32 Hz),1.70-1.96 (6H, m), 2.08-2.22 (1H, m), 2.22-2.36 (2H, m), 2.36-2.47 (1H,m), 2.96 (1H, dd, J=9.27, 8.30 Hz), 3.10 (1H, dd, J=,9.27, 8.79 Hz),3.55-3.62 (1H, m), 4.28 (1H, d, J=9.77 Hz), 5.46 (1H, q, J=7.32 Hz),7.25-7.35 (5H, m)

REFERENCE EXAMPLE 203-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine(isomer B1)

In an atmosphere of nitrogen, 1 M borane-tetrahydrofuran complexsolution (5.6 ml) was added dropwise to tetrahydrofuran solution (15 ml)of4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2pyrrolidone(isomer B1) (700 mg, 1.88 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 13 hours. The solvent was evaporatedunder a reduced pressure, and the resulting residue was mixed with 80%aqueous ethanol (15 ml) and triethylamine (3 ml) and heated under refluxfor 4 hours. After cooling, the solvent was evaporated under a reducedpressure, and the thus obtained residue was mixed with chloroform (30ml), washed with water (10 ml) and saturated sodium chloride aqueoussolution (10 ml) and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the thus obtainedresidue was applied to a silica gel column chromatography and elutedwith chloroform:methanol=20:1, thereby obtaining 565 mg (84%) of thetitle compound as colorless crystals.

¹H-NMR (400 MHz, CDCl₃) δ1.36 (3H, d, J=6.84 Hz), 1.45 (9H, s),1.66-1.95 (7H, m), 2.05-2.22 (2H, m), 2.22-2.34 (1H, m), 2.34-2.45 (2H,m), 3.15 (1H, q, J=6.84 Hz), 3.43-3.53 (1H, m), 4.54-4.62 (1H, m),7.21-7.31 (5H, m)

REFERENCE EXAMPLE 213-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methyl-1-1-(R)-phenylethylpyrrolidine (isomer B2)

In an atmosphere of nitrogen, 1 M borane-tetrahydrofuran complexsolution (6.4 ml) was added dropwise to tetrahydrofuran solution (15 ml)of4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2pyrrolidone(isomer B2) (797 mg, 2.14 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 13 hours. The solvent was evaporatedunder a reduced pressure, and the resulting residue was mixed with 80%aqueous ethanol (15 ml) and triethylamine (3 ml) and heated under refluxfor 4 hours. After cooling, the solvent was evaporated under a reducedpressure, and the thus obtained residue was mixed with chloroform (30ml), washed with water (10 ml) and saturated sodium chloride aqueoussolution (10 ml) and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the thus obtainedresidue was applied to a silica gel column chromatography and elutedwith chloroform:methanol=20:1, thereby obtaining 743 mg (97%) of thetitle compound as colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (3H, d, J=6.83 Hz), 1.46 (9H, s),1.64-1.93 (8H, m), 2.10-2.30 (3H, m), 2.30-2.51 (1H, m), 2.51-2.69 (2H,m), 3.11-3.23 (1H, m), 3.43-3.52 (1H, m), 4.92-5.01 (1H, m), 7.22-7.32(5H, m)

REFERENCE EXAMPLE 223-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methylpyrrolidine(isomer B1)

10% Palladium on carbon catalyst (water content 53.8%, 500 mg) was addedto ethanol (30 ml) solution of3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine(isomer B1) (516 mg, 1.44 mmol), and the mixture was subjected to 5hours of catalytic hydrogenation at an external temperature of 50C in anatmosphere of hydrogen under atmospheric pressure. The reaction solutionwas filtered and the solvent was evaporated under a reduced pressure,thereby obtaining 366 mg (quantitative) of the title compound ascolorless crystals. This product was used in the subsequent reactionwithout purification.

REFERENCE EXAMPLE 233-(R)-[1-(tert-Butoxycarbonyl)amino-1-cyclobutyl]methylpyrrolidine(isomer B2)

10% Palladium on carbon catalyst (water content 53.8%, 650 mg) was addedto ethanol (40 ml) solution of3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]pyrrolidine(isomer B2) (645 mg, 1.80 mmol), and the mixture was subjected to 5hours of catalytic hydrogenation at an external temperature of 50° C. inan atmosphere of hydrogen under atmospheric pressure. The reactionsolution was filtered and the solvent was evaporated under a reducedpressure, thereby obtaining 458 mg (quantitative) of the title compoundas colorless crystals. This product was used in the subsequent reactionwithout purification.

INVENTIVE EXAMPLE 95-Amino-7-[3-(R)-(1-amino-1-cyclobutyl)methyl]pyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4oxoquinoline-3-carboxylicacid (the substituent at the 7-position is originated from B1)

5-Amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (379 mg, 1.20 mmol),3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methylpyrrolidine(isomer B1) (366 mg, 1.44 mmol) and triethylamine (3 ml) were added toacetonitrile (15 ml) and heated under reflux for 8 hours. After cooling,the reaction solution was concentrated under a reduced pressure, and thethus obtained residue was mixed with concentrated hydrochloric acid (15ml) under ice-cooling and then stirred at room temperature for 10minutes. This hydrochloric acid solution was washed with chloroform (20ml×3), and was made alkaline by adding 30% sodium hydroxide aqueoussolution under ice-cooling and then stirred at room temperature for 1hour. This suspension was adjusted to pH 7.6 by adding concentratedhydrochloric acid and 1 N hydrochloric acid and then extracted withchloroform (100 ml×3). The organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under a reduced pressure.Thereafter, the resulting residue was purified by recrystallizing fromethanol-n-hexane and then dried under a reduced pressure, therebyobtaining 386 mg (74%) of the title compound as light yellow crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ: 1.22-1.83 (11H, m), 1.83-1.97 (1H, m),1.97-2.18 (2H, m), 2.18-2.29 (1H, m), 3.07-3.28 (2H, m), 3.35-3.46 (1H,m), 3.53-3.69 (2H, m), 4.78-4.89 (0.5H, m), 4.93-5.02 (0.5H, m), 8.17(1H, s)

Melting point: 175.3-177.6° C. (decomp.)

Elemental analysis data for C₂₂H₂₅F3N₄₀₃ Calcd.: C, 58.66; H, 5.59; N,12.44. Found: C, 58.55; H, 5.61; N, 12.33.

INVENTIVE EXAMPLE 105-Amino-7-[3-(R)-(1-amino-1-cyclobutyl)methyl]pyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (the substituent at the7-position is originated from B2)

5-Amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (474 mg, 1.50 mmol),3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methylpyrrolidine(isomer B2) (458 mg, 1.80 mmol) and triethylamine (4 ml) were added toacetonitrile (20 ml) and heated under reflux for 8 hours. After cooling,the reaction solution was concentrated under a reduced pressure, and thethus obtained residue was mixed with concentrated hydrochloric acid (15ml) under ice-cooling and then stirred at room temperature for 10minutes. This hydrochloric acid solution was washed with chloroform (20ml×3), and was made alkaline by adding 30% sodium hydroxide aqueoussolution under ice-cooling and then stirred at room temperature for 1hour. This suspension was adjusted to pH 7.6 by adding concentratedhydrochloric acid and 1 N hydrochloric acid and then extracted withchloroform (100 ml×3). The organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under a reduced pressure.Thereafter, the resulting residue was purified by recrystallizing fromchloroform-n-hexane and then dried under a reduced pressure, therebyobtaining 386 mg (74%) of the title compound as light yellow crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ: 1.27-1.76 (7H, m), 1.76-1.99 (6H, m),2.17-2.28 (1H, m), 2.34-2.42 (1H, m), 3.36-3.50 (2H, m), 3.50-3.59 (1H,m), 3.64-3.79 (2H, m), 4.79-4.89 (0.5H, m), 4.98-5.06 (0.5H, m), 8.19(1H, s)

Melting point: 198.2-201.4° C. (decomp.)

Elemental analysis data for C₂₂H₂₅F₃N₄O₃. 1.0H₂0 Calcd.: C, 56.40; H,5.81; N, 11.96.

Found: C, 56.34; H, 5.84; N, 11.75.

The antibacterial activity of each compound of the present invention wasmeasured in accordance with the standard method specified by the JapanSociety of Chemotherapy, with the results shown in the following Table 2as MIC values (μg/ml). In this connection, MIC values of levofloxacin(LVFX) and ciprofloxacin (CPEX) are also shown for the sake ofcomparison with the MIC values of the compounds of the presentinvention.

TABLE 2 Compounds (Inventive Example No.) Strains 1 2 4 5 E. coli, NIHJ0.006 0.013 ≦0.003 ≦0.003 S. flexneri, 2A 5503 0.025 0.05 ≦0.003 ≦0.003Pr. vulgaris, 08601 0.2 0.1 0.05 0.013 K. pneumoniae TYPE 1 0.1 0.10.025 0.013 Ser. marcescens, 10100 0.2 0.2 0.05 0.025 Ps. aeruginosa,32104 0.39 0.78 0.1 0.05 PS. aeruginosa, 32121 0.2 0.2 0.05 0.025 X.maltophilia, IID 1275 0.39 0.39 0.05 0.05 S. aureus, FDA 209P 0.0250.025 ≦0.003 ≦0.003 S. epidermidis, 56500 0.1 0.1 ≦0.003 ≦0.003 Str.pyogenes, G-36 0.39 0.2 ≦0.003 ≦0.003 E. faecalis, ATCC 19433 0.2 0.20.025 0.013 S. aureus, 870307 3.13 3.13 0.05 0.025 Str. pneumoniae, J240.1 0.1 ≦0.003 ≦0.003 Compounds (Inventive Example No.) Strains 6 7 8 9E. coli, NIHJ ≦0.003 ≦0.003 0.006 ≦0.003 S. flexneri, 2A 5503 0.006≦0.003 0.1 0.005 Pr. vulgaris, 08601 0.013 0.013 0.05 0.1 K. pneumoniaeTYPE 1 0.05 0.025 0.1 0.025 Ser. marcescens, 10100 0.1 0.05 0.2 0.1 Ps.aeruginosa, 32104 0.1 0.05 0.39 0.2 PS. aeruginosa, 32121 0.05 0.025 0.20.1 X. maltophilia, IID 1275 0.2 0.05 0.2 0.1 S. aureus, FDA 209P ≦0.003≦0.003 0.006 ≦0.003 S. epidermidis, 56500 0.006 ≦0.003 0.025 ≦0.003 Str.pyogenes, G-36 ≦0.003 ≦0.003 0.013 0.013 E. faecalis, ATCC 19433 0.0250.013 0.05 0.05 S. aureus, 870307 0.1 0.025 0.2 0.10 Str. pneumoniae,J24 ≦0.003 ≦0.003 0.006 0.006 Compounds (Inventive Example No.) Strains10 LVFX CPFX E. coli, NIHJ ≦0.003 0.013 ≦0.003 S. flexneri, 2A 5503≦0.003 0.025 0.006 Pr. vulgaris, 08601 0.05 0.13 ≦0.003 K. pneumoniaeTYPE 1 0.025 0.1 0.025 Ser. marcescens, 10100 0.05 0.1 0.025 Ps.aeruginosa, 32104 0.2 0.2 0.05 PS. aeruginosa, 32121 0.2 0.1 0.025 X.maltophilia, IID 1275 0.05 0.39 0.78 S. aureus, FDA 209P ≦0.003 0.2 0.1S. epidermidis, 56500 ≦0.003 0.39 0.2 Str. pyogenes, G-36 ≦0.003 0.21.56 E. faecalis, ATCC 19433 0.013 0.78 0.78 S. aureus, 8703070.05 >6.25 3.13 Str. pneumoniae, J24 ≦0.003 0.78 0.1

INDUSTRIAL APPLICABILITY

The compound of the present invention is possessed of excellentantibacterial action against a broad range of Gram-negative andGram-positive bacteria, particularly showing strong antibacterialactivity against methicillin-resistant Stapylococcus aureus,penicillin-resistant pneumococcus, enterocuccus and the likeGram-positive bacteria and quinolone-resistant bacteria, and is alsopossessed of excellent safety and good pharmacokinetics, such asattenuation of micronuclear test, so that it is useful as anantibacterial compound to be used in the chemotherapy of bacterialinfections.

What is claimed is:
 1. A compound represented by the following formula(I) its salts and hydrates thereof:

wherein R¹ and R² each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms, in which the alkyl group mayhave one or more substituents selected from the group consisting ofhydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbonatoms and an alkyloxy group; n is an integer of 1 to 4; and Q is apartial structure represented by the following formula (Ia):

wherein R³ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms whichmay have a substituent, with the proviso that when R3 is a cyclopropylgroup it is substituted by a halogen compound an aryl group which mayhave a substituent, a heteroaryl group which may have a substituent, analkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1to 6 carbon atoms; R⁴ represents a hydrogen atom or an alkylthio grouphaving 1 to 6 carbon atoms; R⁴ and R³ may form together with a part ofthe mother skeleton a ring structure optionally containing a sulfur atomas a ring constituting atom thereof and optionally having an alkyl grouphaving 1 to 6 carbon atoms as a substituent; R⁵ represents a hydrogenatom, an amino group, a hydroxyl group, a thiol group, a halogenomethylgroup, an alkyl group having 1 to 6 carbon atoms, an alkenyl grouphaving 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atomsor an alkoxyl group having 1 to 6 carbon atoms, in which the amino groupmay have one or more substituents selected from the group consisting ofa formyl group, an alkyl group having 1 to 6 carbon atoms and an acylgroup having 2 to 5 carbon atoms; X¹ represents a halogen atom or ahydrogen atom; A¹ represents a nitrogen atom or a partial structurerepresented by formula (II):

wherein X² represents a hydrogen atom, an amino group, a halogen atom, acyano group, a halogenomethyl group, a halogenamethoxyl group, an alkylgroup having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbonatoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl grouphaving 1 to 6 carbon atoms, in which the amino group may have one ormore substituents selected from the group consisting of a formyl group,an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to5 carbon atoms; and X² and R³ may form together with a part of themother skeleton a ring structure optionally containing an oxygen atom, anitrogen atom or sulfur atom as a ring constituting atom thereof andoptionally having an alkyl group having 1 to 6 carbon atoms as asubstituent; and Y represents a hydrogen atom, a phenyl group, anacetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group,a choline group, a dimethylaminoethyl group, a 5-indanyl group, aphthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms,an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl groupcomposed of an alkylene group having 1 to 6 carbon atoms and a phenylgroup.
 2. A compound, its salts and hydrates thereof according to claim1, wherein Q in the formula (I) is a6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazin-10-ylgroup.
 3. A compound, its salts and hydrates thereof according to claim1, wherein the compound of formula (I) is a stereochemically purecompound.
 4. A compound, its salts and hydrates thereof according toclaim 1, wherein R³ in the formula (I) is a halogenocyclopropyl group.5. A compound, its salts and hydrates thereof according to claim 1,wherein the halogenocyclopropyl group in the formula (I) is a1,2-cis-halogenocyclopropyl group.
 6. A compound, its salts and hydratesthereof according to claim 5, wherein the halogenocyclopropyl group inthe formula (I) is a stereochemically pure substituent.
 7. A compound,its salts and hydrates thereof according to claim 6, wherein thehalogenocyclopropyl group in the formula (I) is a(1R,2S)-2-halogenocyclopropyl group.
 8. A compound, its salts andhydrates thereof according to claim 7, wherein the halogen atom of thehalogenocyclopropyl group in the formula (I) is a fluorine atom.
 9. Acompound, its salts and hydrates thereof according to claim 8, whereinthe compound of formula (I) is a stereochemically pure compound.
 10. Acompound, its salts and hydrates thereof according to claim 1, wherein nin the formula (I) is
 1. 11. A compound, its salts and hydrates thereofaccording to claim 10, wherein the compound of formula (I) is astereochemically pure compound. 12.7-[3-[1-(S)-Amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts and hydrates thereof. 13.5-Amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid, its salts and hydrates thereof. 14.5-Amino-7-[3-[1-(S)-amino-1-cyclopropyl]methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, its salts and hydrates thereof.
 15. A compound, its salts andhydrates thereof according to claim 1, wherein Y is a hydrogen atom. 16.A drug containing the compound, its salts and hydrates thereof describedin any one of claims 1 to 15 as an active ingredient and apharmaceutically acceptable carrier.
 17. An antibacterial containing thecompound, its salts and hydrates thereof described in any one of claims1 to 15 as an active ingredient and a pharmaceutically acceptablecarrier.